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Review ARTICLE

Front. Genet., 13 June 2017 | https://doi.org/10.3389/fgene.2017.00077

Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models

Malabika Maulik1, Swarup Mitra1, Abel Bult-Ito2, Barbara E. Taylor3 and Elena M. Vayndorf4*
  • 1Department of Chemistry and Biochemistry, University of Alaska Fairbanks, Fairbanks, AK, United States
  • 2Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, United States
  • 3Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States
  • 4Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, United States

Parkinson's disease (PD) is a neurodegenerative disorder with symptoms that progressively worsen with age. Pathologically, PD is characterized by the aggregation of α-synuclein in cells of the substantia nigra in the brain and loss of dopaminergic neurons. This pathology is associated with impaired movement and reduced cognitive function. The etiology of PD can be attributed to a combination of environmental and genetic factors. A popular animal model, the nematode roundworm Caenorhabditis elegans, has been frequently used to study the role of genetic and environmental factors in the molecular pathology and behavioral phenotypes associated with PD. The current review summarizes cellular markers and behavioral phenotypes in transgenic and toxin-induced PD models of C. elegans.

Introduction

Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder after Alzheimer's disease. It affects seven to 10 million individuals worldwide (Beitz, 2014), with the mean age of onset at 60 years, where 1% of all individuals over the age of 60 and 4% of those over 80 years present with PD symptoms. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (nigrostriatal pathway) area of the brain (Michel et al., 2013; Kalia and Lang, 2015). At the cellular level, the hallmarks of PD include intra-cytoplasmic inclusions that contain a disease-specific protein: α-synuclein, a primary component of Lewy bodies and dystrophic Lewy neurites in neurons (Bethlem and Den Hartog Jager, 1960; Spillantini et al., 1997; Dickson, 2012). The loss of dopaminergic neurons results in motor impairments, including tremors, hypokinesia, bradykinesia, rigidity, and postural instability (Samii et al., 2004; Jankovic, 2008; Yao S. C. et al., 2013). Other recognizable motor deficits include festination, speech and swallowing disorders, and handwriting in small letters (Jankovic, 2008; Russell et al., 2010). Since PD affects neurons in the central and peripheral nervous systems, patients typically also exhibit multiple non-motor symptoms including anxiety, depression, memory loss, and olfactory deficits (Doty, 2012; Grover et al., 2015). While the cause of PD is currently unknown, genetic (familial) and environmental (sporadic) triggers are two major factors that play a role in the development of the disease, with the environment accounting for over two-thirds of all cases (Fleming et al., 1994; Warner and Schapira, 2003; Gatto et al., 2010; Goldman et al., 2012; Trinh and Farrer, 2013). The predisposition to both sporadic and familial types of PD is linked to multiple genes whose function is an area of active investigation. These include α-synuclein, LRRK2, PARK2, DJ-1, GBA, UCHL1 and others. For example, a mutation in the glucocerebrosidase (GBA) gene, which codes for an enzyme essential for metabolism of lysosomal substrates is linked to the pathogenesis of sporadic PD (Gegg et al., 2012). Similarly, a mutation in the ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), an enzyme which is involved in the removal and recycling of ubiquitin molecules from degraded proteins, and ligation of ubiquitin to proteins to mark them for degradation, has been linked to the early-onset of familial PD (Dawson and Dawson, 2003). The identification of these and other genes, and the discovery that certain toxins such as MPTP, 6-OHDA, and paraquat lead to PD symptoms, has informed the development of genetic and toxin-induced PD models (Polymeropoulos et al., 1997; Bonifati et al., 2003; Paisán-Ruiz et al., 2004; Valente et al., 2004; Zimprich et al., 2004) and resulted in a better understanding of disease etiology, pathology, and molecular mechanisms (Harrington et al., 2010; Whitworth, 2011; Blesa et al., 2012a).

In mammalian models, genetically modified rodents have proven critical to the understanding of PD pathology and the exploration of new therapeutic strategies (Ribeiro et al., 2013). Rodent models display many of the clinical features of PD such as the loss of dopaminergic neurons (Meredith and Rademacher, 2011; Thiele et al., 2012; Torres and Dunnett, 2012), neurochemical changes in dopamine transmission and signaling, motor dysfunction, and non-motor symptoms including cognitive decline, autonomic dysfunction, depression, and hyposmia (Taylor et al., 2010; Schirinzi et al., 2016). However, these models do not mimic some important pathological hallmarks of the disease (Fleming and Chesselet, 2006; Visanji et al., 2016) such as the gradual neurodegenerative process, gross morphological abnormalities and overt motor alterations (Yue and Lachenmayer, 2011; Ribeiro et al., 2013; Schirinzi et al., 2016). Moreover, gene editing techniques in rodents involve complex experimental design, significant time investment and considerable expense. Environmental toxin-induced rodent models have also provided valuable information about PD pathology. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a severe and permanent parkinsonism syndrome that features the major symptoms of human PD including rigidity, tremor, postural instability, and slowness of movement (Liou et al., 1997; Bove et al., 2005). In addition, environmental exposure to paraquat is a risk factor for PD; paraquat administration increases α-synuclein levels and α-synuclein-positive inclusion bodies in substantia nigra neurons (Manning-Bog et al., 2002). A major drawback of toxin-induced models is that acutely induced neurodegeneration investigates a phase of PD when nearly 70–80% of dopaminergic neurons are already lost, thus lacking the age-dependent progressive lesions and Lewy bodies that are typical of human patients (Blandini and Armentero, 2012; Schirinzi et al., 2016).

Non-mammalian, including invertebrate models such as Drosophila melanogaster and Caenorhabditis elegans are also useful in understanding the molecular mechanisms of PD (Jagmag et al., 2015). These models facilitate investigations of PD-associated molecular signaling pathways and first-round screening that can be followed-up in mammalian models (Jagmag et al., 2015). For example, D. melanogaster transgenic models have helped clarify the role of PD candidate genes in mitochondrial physiology (Venderova et al., 2009; Dawson et al., 2010; Guo, 2012). Similarly, the nematode C. elegans is a useful model organism for studying healthy and abnormal neuronal aging, including cellular symptoms of PD. Caenorhabditis elegans share many conserved cellular pathways and mechanisms with mammals, including humans (Consortium, 1998; Lai et al., 2000; Shaye and Greenwald, 2011). These cellular pathways can be genetically manipulated using RNA interference (RNAi) by gene-specific bacterial feeding (Fire et al., 1998), which enables rapid screening of target genes (Jorgensen and Mango, 2002; Wang and Sherwood, 2011). RNAi screening is an important tool for predicting pathogenic mechanisms before moving to complex organisms for further investigation (Jorgensen and Mango, 2002; Leung et al., 2008; O'Reilly et al., 2014). Despite major anatomical differences from humans, the C. elegans nervous system consists of a circumpharyngeal nerve ring, and contains key cellular and molecular features of mammalian neurons, including conserved neurotransmitter systems (dopamine, GABA, acetylcholine, serotonin, etc.), receptors, axon guidance molecules, ion channels, and synaptic features. Although α-synuclein is not endogenous to C. elegans, expression of this human PD-associated protein in C. elegans dopaminergic neurons results in neurodegeneration in an age-dependent manner (Lakso et al., 2003; Kuwahara et al., 2006; Hamamichi et al., 2008; Karpinar et al., 2009). Moreover, most familial PD genes such as PINK1, PARK, DJ-1, and LRRK2 have at least one C. elegans homolog (Sakaguchi-Nakashima et al., 2007; Sämann et al., 2009; Chege and Mccoll, 2014; Lee and Cannon, 2015). Hermaphroditic C. elegans have 302 neurons, of which eight (ADEL, ADER, CEPDL, CEPDR, CEPVL, CEPVR, PDEL, and PDER) are dopaminergic such as those implicated in PD in humans (Sulston et al., 1975). Four dopamine receptors (DOP-1, DOP-2, DOP-3, and DOP-4) have been identified in C. elegans, including homologs of each of the two classes of mammalian dopamine receptors (D1- and D2-like) (Chase and Koelle, 2007). Caenorhabditis elegans neuronal morphology can be linked to functional abnormalities for easy visualization and quantification making it possible to establish a correlation between behaviors and aberrations in the target neurons, which are induced by mutations or exposure to toxins (Nass et al., 2002; Toth et al., 2012; Scerbak et al., 2014; Vayndorf et al., 2016). In addition, C. elegans have low maintenance costs, and their shorter lifespan (2–3 weeks) reduces the time needed for each experiment. These advantages make C. elegans a valuable model system for genetic and chemical screening, and pre-clinical research. In contrast, the limitations of a C. elegans PD model include a lack of defined organs, including the complex brain structure seen in humans and, therefore, the inability to recapitulate the same set of complex interactions involving various brain cells and tissues seen in human PD patients (Tissenbaum, 2015). In addition, the mostly impermeable cuticle and inability of intestinal cells to take up some types of chemicals may require high exposure doses to affect the animal's physiology (Leung et al., 2008; Tissenbaum, 2015). Despite these limitations, C. elegans have proven useful in aging research (Tissenbaum, 2015) and numerous studies have used C. elegans to investigate the cellular mechanisms associated with PD (see Table 1). The aim of this review is to highlight the genetic and chemical tools and reagents, as well as genetic, biochemical, physiological, and behavioral endpoints associated with investigating the cellular and behavioral symptoms of PD in C. elegans.

TABLE 1
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Table 1. Strains of C. elegans commonly used to study PD pathology.

Caenorhabditis elegans Models of Parkinson's Disease

In this section, we discuss the link between genetic and environmental factors and PD. All existing C. elegans models are the result of genetic manipulation or exposure to toxic chemicals.

Genetic C. elegans Models Linked to Familial PD

Over the last decade, transgenic models of C. elegans have been successfully used to study PD-like pathologies and behaviors (Caldwell and Caldwell, 2008; Harrington et al., 2010). In humans, monogenic forms of PD, caused by a single gene mutation in a dominant or recessive fashion, are well-established, though relatively rare types of the disease. They account for approximately 30% of the familial cases (Klein and Westenberger, 2012).

Alpha-Synuclein

Alpha-synuclein is a small, highly soluble, predominantly presynaptic cytoplasmic protein composed of 140 amino acids with three domains. It is highly conserved in vertebrates and has been implicated in PD and other synucleinopathies (Snead and Eliezer, 2014). In humans, α-synuclein is largely present in the brain, with smaller amounts also present in the heart, muscles, and other tissues (Xu and Pu, 2016). While the normal physiological structure and function of α-synuclein is unclear, studies suggest that it is important for compartmentalization, storage, and recycling of neurotransmitters (Lee et al., 2002). In addition, α-synuclein can regulate a variety of enzymes, is thought to increase the number of dopamine transporters, and has molecular chaperone activity, which is linked to neurotransmitter release (Nemani et al., 2010). The α-synuclein gene, SNCA, is causatively related to PD and its mutation was the first gene to be linked to the disease (Polymeropoulos et al., 1997). Mutations in SNCA, including rare point mutations in the N-terminal domain of α-synuclein as well as duplications and triplications of wild-type α-synuclein cause familial forms of PD in humans (Ross et al., 2008; Klein and Westenberger, 2012; Singleton et al., 2013).

Caenorhabditis elegans do not have an α-synuclein homolog. Thus, to study the pathogenicity of α-synuclein overexpression and aggregation in PD, several transgenic C. elegans strains with human α-synuclein have been created. These strains are particularly useful for studying the toxicity of protein aggregates, and cellular and behavioral abnormalities (Hamamichi et al., 2008; van Ham et al., 2008). Strains OW13 ([unc-54p::α-synuclein::YFP + unc-119(+)]), NL5901 ([unc-54p::α-synuclein::YFP+unc-119(+)]), and DDP1 (uonEx1[unc-54p::α-synuclein::CFP + unc-54::α-synuclein::YFP(Venus)] express α-synuclein in body wall muscle cells (van Ham et al., 2008; Bodhicharla et al., 2012). In these strains, the human α-synuclein gene is fused to yellow fluorescent protein (YFP), which drives the expression of α-synuclein in the body wall muscle cells under the control of the unc-54 promoter (Hamamichi et al., 2008; van Ham et al., 2008; Bodhicharla et al., 2012). These strains have been used to study α-synuclein aggregation, changes in movement, animal behavior and genes that modulate these and other PD-related hallmarks. For example, the brains of PD patients contain electron-dense filamentous and granular protein inclusions filled with aggregated protein. Similarly, C. elegans body wall muscle cells accumulate clearly visible aggregates with age, providing a defined target for screening of candidate genes via RNAi. Van Ham and colleagues have identified 80 suppressors of inclusion formation, with 49 of these genes having an established human ortholog. These authors also found an increase in the number of “immobile” inclusions relative to “mobile” inclusions during aging (van Ham et al., 2008). The accumulation of α-synuclein aggregates in these strains is associated with locomotory and movement impairments (Bodhicharla et al., 2012) providing additional screening targets. All three strains containing α-synuclein in body wall muscle cells are available from the Caenorhabditis Genetics Center at the University of Minnesota for a nominal shipping charge (see Table 1).

In addition to strains that overexpress α-synuclein in body wall muscle cells, strains that overexpress wild-type or mutant (A53T) human α-synuclein in dopaminergic neurons have been generated by multiple research groups (Lakso et al., 2003; Kuwahara et al., 2006, 2008; Cooper et al., 2015). In these models, the dopamine transporter promoter dat-1 is fused to GFP, following co-expression of wild-type or mutant (A53T) α-synuclein and GFP. The A53T mutation causes a change from alanine to threonine at position 53, is highly penetrant, and is associated with the autosomal dominant form of PD (Polymeropoulos et al., 1997; Lakso et al., 2003). In C. elegans expressing both wild-type and mutant α-synuclein, neuronal abnormalities, including accumulation of aggregates and cell loss were observed in some or all dopaminergic neurons, typically in an age-dependent manner (Lakso et al., 2003; Kuwahara et al., 2006, 2008; Cooper et al., 2015). Moreover, neurodegeneration of dopamine neurons was enhanced in transgenic lines in which mRNA levels of α-synuclein were expressed at higher levels (Dexter et al., 2012).

In humans, fibrils of α-synuclein aggregate to form Lewy bodies, intracellular inclusions of protein complexes made of α-synuclein aggregates and other components such as neurofilaments, lipids and membrane materials (Spillantini et al., 1997; van Ham et al., 2008). Lewy bodies are a major hallmark of PD. When human α-synuclein is expressed in C. elegans dopaminergic neurons, expression as inclusion bodies is rare and aggregation of α-synuclein is not observed in Western blots (Lakso et al., 2003). However, α-synuclein misfolding can be followed in body wall muscle cells as translational fusion YFP inclusions. In strains NL5901, OW13, and DDP1, which express these inclusions, α-synuclein aggregates and leads to toxicity with age. Importantly, large-scale reverse genetic RNAi screens have revealed enhancers and suppressors of α-synuclein misfolding, including genes that protect against α-synuclein neurodegeneration when co-expressed with α-synuclein in dopaminergic neurons (Hamamichi et al., 2008; van Ham et al., 2008).

LRK-1 and PINK-1

In PD patients, mutations in the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for both familial and sporadic PD, accounting for 4% of familial and 1% of sporadic PD across all populations (Healy et al., 2008). Mutations are prevalent within the GTPase (R1441C/G) and kinase (G2019S) domains of LRRK2. The normal function of LRRK2 is an area of active investigation, with research suggesting remarkably diverse pathways including regulation of transcription (Kanao et al., 2010), translation (Imai et al., 2008), apoptosis (Ho et al., 2009), and mitochondrial function (Smith et al., 2005). LRRK2 is consistently located at intracellular membranous structures including mitochondria (West et al., 2005; Biskup et al., 2006; Gloeckner et al., 2006; Hatano et al., 2007), the endo-lysosomal system (Alegre-Abarrategui et al., 2009), the endoplasmic reticulum (ER) (Gloeckner et al., 2006; Vitte et al., 2010), and Golgi C. elegans (Biskup et al., 2006; Gloeckner et al., 2006; Hatano et al., 2007).

In C. elegans, the lrk-1 gene is homologous to mammalian LRRK1 and LRRK2, human and mouse leucine-rich repeat kinases, respectively. LRRK1 is necessary for polarized localization of synaptic vesicle proteins to presynaptic regions (Shin et al., 2008; Esposito et al., 2012). LRK-1 is expressed in many tissues, including head and tail neurons, hypodermis, intestine and muscles, and localizes to the Golgi apparatus (Sämann et al., 2009).

Two types of C. elegans genetic models have been used to study the leucine-rich repeat kinase and its contribution to PD-like symptoms. In the first, two lrk-1 mutant strains that each contain severe loss-of-function alleles (tm1898) and (km41) that express truncated LRK-1 proteins consisting of the N-terminal ankyrin repeat, have been used to study pink-1, a PTEN-induced kinase and homolog of the PD-related human PINK1. Both alleles of lrk-1 suppressed the paraquat sensitivity of pink-1(tm1779) mutants to restore survival to wild-type levels (paraquat toxicity is detailed in the Insecticides and Herbicides subsection of the Toxin-Induced Models section below). Lrk-1(tm1898) also suppressed the mitochondrial cristae defects of pink-1(tm1779) animals to wild-type levels suggesting that genetic deletion of lrk-1 could compensate for both the oxidative stress sensitivity and the mitochondrial integrity observed in a pink-1 loss-of-function allele. Interestingly, both C. elegans lrk-1 allele mutants are not sensitive to paraquat and have an intact mitochondrial cristae, but exhibit an enhanced sensitivity to ER stress that can be rescued by pink-1(tml779). Moreover, both lrk-1 mutations suppressed pink-1(tml779)-mediated axon guidance defects suggesting that LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth (Sämann et al., 2009). These results link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes involved in PD, and highlight stress sensitivity and cytoskeletal defects as factors that may contribute to the onset of PD.

In the second approach, human wild-type and mutant G2019S and R1441C LRRK2 have been overexpressed in dopaminergic neurons of C. elegans under the expression of the dopamine transporter dat-1 promoter co-injected with dat-1p::GFP to generate [dat-1p::GFP, dat-1p::LRRK2(WT), lin-15(+)] and [dat-1p::GFP, dat-1p::LRRK2(G2019S), lin-15(+)] (Yao et al., 2010b; Yao S. C. et al., 2013; Cooper et al., 2015). Overexpression of these LRRK2 proteins caused age-dependent degeneration of dopaminergic neurons, behavioral deficits, locomotory dysfunction, and reduced dopamine levels in transgenic models of C. elegans. In comparison to the overexpression of wild-type LRRK2, R1441C and G2019S mutants showed more severe phenotypes. Treatment with exogenous dopamine rescued the LRRK2-induced behavioral and locomotory deficits (Yao et al., 2010b; Yao S. C. et al., 2013).

PDR-1

Some autosomal recessive forms of PD are associated with mutations in PARKIN (PARK2), an E3 ubiquitin ligase that is important for neuronal protein homeostasis (Lücking et al., 2000; Bonifati et al., 2003; Valente et al., 2004; Trempe and Fon, 2013). In C. elegans, the PARK2 homolog pdr-1 is an essential component in the degradation machinery during the response to proteotoxic stressors (Springer et al., 2005). Specifically, pdr-1 was shown to play a role in the UPR pathway, and co-expression of mutant α-synuclein A53T and truncated pdr-1 exacerbated mutant α-synuclein-induced toxicity in a UPR-independent way (Springer et al., 2005). Previously, Morimoto and colleagues showed that heat shock proteins and molecular chaperones play an important role in maintaining protein homeostasis (Morimoto et al., 1997; Morimoto, 2008). Failure of these proteins to prevent misfolding and clearance of toxic aggregated proteins disrupts protein homeostasis and contributes to aging in C. elegans (Satyal et al., 2000; David et al., 2010). Conversely, overexpression of chaperones can improve proteostasis and reduce aggregation in protein misfolding diseases (Calamini et al., 2011). Recently, a new proteostasis mechanism of protein clearance for toxic, misfolded, and aggregated proteins in C. elegans neurons was proposed by Melentijevic et al. (2017). In this model, extracellular vesicles called exophers pinch off from the soma of some types of neurons to jettison toxic protein aggregates and damaged organelles including mitochondria and lysosomes for downstream degradation. The authors note that fluorescently-labeled touch receptor neurons of animals that have a pdr-1(gk448) mutant genetic background or those treated with pink-1 RNAi produce significantly more exophers than animals of a wild-type background (Melentijevic et al., 2017). These observations suggest that impaired mitochondrial genes linked to PD can increase exopher production and provide a potential new area of investigation for cellular hallmarks of PD (Melentijevic et al., 2017).

DJR-1.1 and DJR-1.2

In humans, the DJ-1 gene is causally linked to familial PD (Bonifati et al., 2003). First identified as an oncogene (Nagakubo et al., 1997), its functions include transcriptional regulation, antioxidant activity (in particular after toxic insults), chaperone activity, protease cleavage, and mitochondrial regulation. DJ-1 activity is regulated by its oxidative status and excess oxidation renders the protein inactive, a hallmark observed in patients with sporadic and familial PD as well as some patients with Alzheimer's disease (Choi et al., 2006). DJ-1 can also act as a stress sensor and its expression is increased with stresses such as oxidative stress (Ariga et al., 2013). C. elegans have two DJ-1 orthologs: djr-1.1, and djr-1.2; both encode a type of glyoxylase. This enzyme facilitates the removal of α-oxoaldehydes, byproducts of glucose oxidation, lipid peroxidation and DNA oxidation, which can react non-enzymatically with amino groups of proteins to form advanced glycation end-products (AGEs), which are linked to PD (Lee et al., 2012). DJR-1.2 localizes to the cytosol and is expressed throughout life in a variety of cell and tissue types such as head neurons (including dopaminergic neurons), pharyngeal muscle, the ventral nerve cord, spermatheca, excretory canal cells, and coelomocytes. Manganese (Mn) (discussed in more detail in the Manganese subsection of the Toxin-Induced Models section below) is an essential nutrient needed for protein and energy metabolism, metabolic regulation, protection from reactive oxygen species (ROS), and enzymes function. Environmental exposure to large doses of Mn can lead to manganism, which shares multiple features with PD and is an established risk factor for PD occurrence (Aschner et al., 2009). Previously, Benedetto and colleagues have shown that intracellular dopamine can lead to Mn-induced dopaminergic neurodegeneration in C. elegans, and that this process depends on a functional dopamine-reuptake transporter (DAT-1) and is associated with elevated oxidative stress and reduced lifespan (Benedetto et al., 2010). Neuronal expression of DJR-1.2 in the head and ventral nerve chord neurons is elevated after exposure to acute Mn (Chen P. et al., 2015) and djr-1.2 is protective against Mn-induced dopaminergic toxicity in an age-dependent manner (Chen P. et al., 2015). Specifically, deletion of djr-1.2 decreases survival and dopamine-dependent dauer movement behavior after Mn exposure, and lifespan could be rescued by overexpression of djr-1.2 or daf-16 (Chen P. et al., 2015) mitigating Mn-dependent lifespan reduction and dopamine signaling alterations, involving DAF-2/DAF-16 signaling. The C. elegans djr-1.1, also orthologous to DJ-1, localizes to the intestine and plays a primary role in protecting animals from glyoxal. Treatment of djr-1.1, and to a lesser extent djr-1.2 deletion animals with glyoxal significantly improved their survival suggesting that this gene can protect animals from glyoxal-induced death (Lee et al., 2012).

DAT-1 and CAT-2

The human dopamine transporter (DAT) pumps dopamine out of the synapse back into the cytosol where other transporters deliver it to specialized vesicles for storage and eventual release. Reuptake via DAT is a major mechanism through which dopamine is cleared from synapses. Dopaminergic neurons in the substantia nigra of PD patients express higher levels of DAT (Uhl, 1998; Nass and Blakely, 2003) and greater DAT levels are linked to reduced dopamine turnover and smaller changes in synaptic dopamine concentration (Longo et al., 2017). This implies that an important functional role of DAT is to maintain relatively constant synaptic dopamine levels and to preserve dopamine in nerve terminals (Sossi et al., 2007, 2009; Lee et al., 2008).

The eight dopaminergic neurons of C. elegans have been fluorescently tagged with GFP using the DAT-1 promoter in neuronal transgenic strains BZ555 ([dat-1p::GFP]), BY200 [dat-1p::GFP, pRF4(rol-6(su1006)], and TG2435 ([dat-1p::GFP + rol-6(su1006)]) (Nass et al., 2002; Pu and Le, 2008; Masoudi et al., 2014; Cooper et al., 2015). Studying these cells in a genetic background of overexpressed α-synuclein or after treatment with the environmental toxin 6-OHDA has revealed that DA neurons degenerate with age and identified alleles that confer 6-OHDA resistance (Nass et al., 2005; Hamamichi et al., 2008).

The C. elegans cat-2 gene encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine synthesis (Sulston et al., 1975; Omura et al., 2012; Masoudi et al., 2014). Overexpression of CAT-2 in C. elegans leads to age-dependent degeneration of dopaminergic neurons (Cao et al., 2005; Masoudi et al., 2014). Table 1 summarizes the most commonly used C. elegans strains for studying the molecular pathology and behavioral phenotypes of PD.

Toxin-Induced Models

MPTP and 6-OHDA

In addition to transgenic C. elegans models involving the overexpression or mutation of PD-linked genes to study the genetic causes of PD, environmental agents have also been used to study PD-related neuronal degeneration and cell death (Nass et al., 2002; Pu and Le, 2008; Ali and Rajini, 2012; Zhou et al., 2013). Previous studies have modeled the motor aspects of PD using in vivo exposure to toxins that cause an overload of ROS and disrupt the electron transport chain in mitochondria leading to neuronal abnormalities and eventually cell death (Varcin et al., 2012; Dias et al., 2013; Hwang, 2013; Chege and Mccoll, 2014). The best studied neurodegeneration-inducing chemicals in C. elegans PD models are the toxins 6-OHDA (6-hydroxydopamine) and MPTP (1-methyl-1, 2, 3, 6-tetrahydropyidine) (Nass et al., 2001 Chakraborty et al., 2013; Chen P. et al., 2015).

MPTP was first identified as a PD-causing neurotoxin in humans in the 1980s after drug addicts in California inadvertently administered the agent in synthetic heroin (Langston et al., 1983). MPTP is highly lipophilic and can cross the blood brain barrier. In the brain, it is converted to 1-methyl-4-phenylpyridinium ion (MPP+) by glial monoamine oxidase B (Smeyne et al., 2005). MPP+ exerts neuronal toxicity by inhibiting complex I of the mitochondrial electron transport chain to induce mitochondrial dysfunction, decreasing the mitochondrial DNA content, and impairing autophagic degradation (Zhu et al., 2012; Miyara et al., 2016). Braungart and colleagues showed that wild-type C. elegans treated with 1.4 mM MPP+ at the L1 stage display developmental delays and exhibit an uncoordinated behavioral phenotype (twitcher and coiler) 3 days after treatment compared to untreated controls (Braungart et al., 2004). Further, MPP+ was actively taken up by the dopamine transporter and selectively degenerated dopaminergic neurons. In a screen that tested compounds for ameliorating the toxic effects of MPP+, two dopamine receptor agonists, lisuride and apomorphine, improved mobility and reduced coiling with no effect on development and mobility of wild-type animals, suggesting that improved symptoms resulted from the reduction of MPP+ toxicity (Braungart et al., 2004). Treating cat-2::GFP animals with 1.0 and 1.5 mM MPP+, degenerated dopaminergic neurons and led to reduced mobility (Braungart et al., 2004).

6-OHDA was first isolated in the 1950s (Senoh and Witkop, 1959; Senoh et al., 1959); it has a chemical structure similar to dopamine but with the addition of a hydroxyl group that makes it toxic to dopaminergic neurons (Blesa et al., 2012b). In PD research, the administration of 6-OHDA causes mitochondrial failure by inhibiting complex I of the mitochondrial electron transport chain. This results in ATP depletion and elevated oxidative stress, which ultimately leads to dopamine neuron damage (Glinka et al., 1997, 1998; Nass et al., 2002; Meredith et al., 2008; Pu and Le, 2008; Meredith and Rademacher, 2011; Ali and Rajini, 2012; Thiele et al., 2012). In C. elegans, 6-OHDA administration leads to the loss of GFP-labeled dopaminergic cell bodies and processes (Masoudi et al., 2014). Interestingly, two dopamine D2 receptor agonists, bromocriptine and quinpirole, ameliorate 6-OHDA toxicity in a dose-dependent manner via receptor-independent mechanisms (Marvanova and Nichols, 2007). CAT-2 overexpression confers resistance to 6-OHDA in wild-type and CAT-2 mutant backgrounds possibly due to reduced 6-OHDA uptake into dopaminergic neurons when excess dopamine is present (Masoudi et al., 2014). Due to the conservation between mammalian and C. elegans dopamine receptors, these and other results from toxin-induced neurodegeneration studies in C. elegans may help shed light on novel mechanisms leading to dopaminergic neuroprotection (Chen Y. M. et al., 2015).

Insecticides and Herbicides

Rotenone (a broad spectrum insecticide), paraquat (an herbicide), and several other insecticides have been used to induce PD-like pathology in C. elegans (Ved et al., 2005; Settivari et al., 2009; VanDuyn et al., 2010, 2013; Jadiya and Nazir, 2012; Jadiya et al., 2012; Zhou et al., 2013; Gonzalez-Hunt et al., 2014). Both paraquat and rotenone trigger excessive ROS production in neurons, which leads to cellular damage (Ved et al., 2005; Miller et al., 2007; Tanner et al., 2010, 2011; Spivey, 2011; Zhou et al., 2013). Caenorhabditis elegans strains including BY250 (dat-1p:GFP), BZ555 (dat-1p:GFP), and UA57 ([dat-1p::GFP+dat-1p::cat-2]) can be exposed to these toxins to visualize and quantify abnormalities in neuronal morphology (Nass et al., 2002; Pu and Le, 2008; Liu et al., 2015; Li H. et al., 2016). Jadiya and colleagues selected specific neurotoxins to represent different pesticide classes including a botanical, an herbicide, a pesticide, a fungicide, an organophosphate, and a pyrethroid. The authors found that in strain NL5901 ([unc-54p::α-synuclein::YFP+unc-119(+)]), superoxide dismutase and heat shock protein genes exhibit a unique pattern of expression for each pesticide class (Jadiya and Nazir, 2012; Jadiya et al., 2012). In addition, rotenone significantly increased α-synuclein aggregation and oxidative stress, while reducing mitochondrial and lipid content in NL5901 animals (Jadiya and Nazir, 2012).

Manganese

Mn is an essential transition metal required for growth, development and cellular homeostasis (Prohaska, 1987; Takeda et al., 2003). It is a co-factor for multiple enzymes such as Mn superoxide dismutase, pyruvate carboxylase, arginase, and glutamine synthase, and can substitute for magnesium (Mg) in enzymatic reactions catalyzed by kinases (Horning et al., 2015). However, inhaling toxic levels of Mn can lead to nasal and pulmonary inflammation, renal dysfunction, and neurodegeneration (Aschner and Aschner, 1991). For example, occupational exposure through Mn mining, steel manufacturing, and welding are linked to increased risk for parkinsonian syndrome (Myers et al., 2003). Specifically, exposure to toxic levels of Mn can cause oxidative injury in the substantia nigra, the loss of dopaminergic neurons and phenotypes such as tremor, rigidity, and bradykinesia (Calne et al., 1994; Olanow, 2004). In C. elegans, Benedetto et al. found that extracellular and not intracellular dopamine is responsible for Mn-induced dopaminergic neurodegeneration, and that this process depends on a functional DAT-1 receptor and is linked to oxidative stress and lifespan reduction. Overexpression of the antioxidant transcription factor, SKN-1, reduces Mn toxicity, and dopamine-dependent Mn toxicity requires the NADPH dual-oxidase BLI-3. The authors proposed that in vivo BLI-3 (which has over 99% homology to the human DUOX genes) facilitates the conversion of extracellular dopamine into toxic reactive species, which get taken up by DAT-1 in dopaminergic neurons and cause oxidative stress and cell degeneration (Benedetto et al., 2010). Mn neurotoxicity was also studied in genetic DJ-1 models of C. elegans exposed to Mn (Chen P. et al., 2015); the results suggest that DJ-1 has a protective role and improves lifespan in Mn-exposed nematodes in an age-dependent manner.

Markers of Pathology in Genetic and Toxin-Induced PD C. elegans Models

Alpha-Synuclein Expression

To model α-synuclein aggregation and accumulation in vivo, researchers have generated transgenic C. elegans strains that express the human α-synuclein gene in body wall muscle cells and in neurons (Table 1). In these models, increased or decreased fluorescence intensity associated with YFP linked to α-synuclein can be quantified to determine the levels of protein expression (Jadiya et al., 2011; Jadiya and Nazir, 2012; Fatima et al., 2014; Fu et al., 2014a; Chen Y. M. et al., 2015; Liu et al., 2015). Loss of fluorescence intensity indicates reduced protein expression, whereas increased fluorescence indicates increased α-synuclein expression. Such changes in protein expression can be visualized using microscopy (Figure 1) and analyzed using freely available programs such as FIJI (Schindelin et al., 2012). Alterations in protein expression can also be assessed using techniques such as fluorescence resonance energy transfer (FRET) or fluorescence recovery after photobleaching (FRAP) (Bodhicharla et al., 2012).

FIGURE 1
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Figure 1. Representative image of the head region of a day-7 adult of strain NL5901 ([unc-54p::α-synuclein::YFP+unc-119]), maintained at 22°C, showing α-synuclein protein expression in the body wall muscle cells. The white arrow indicates one of multiple visible protein aggregates. Scale bar, 50 μm; magnification, 50×. (Original image taken by the authors for this paper on a Zeiss LSM 510 laser scanning confocal microscope).

Neuronal Morphology

Aberrant neuronal morphologies caused by exposure to neurotoxins or heavy metals can be visualized using fluorescence microscopy and quantified by counting the types and frequencies of aberrations. Such investigations typically focus on dopaminergic neurons of the head, i.e., the four CEPs and two ADEs (Figures 2a,b). Aberrant morphologies include the loss of neuronal cell bodies (Figure 2c), the absence of neuronal processes, broken neurites (Figure 2d), shrinking of dendritic endings, and the appearance of vacuoles (Nass et al., 2002; Pu and Le, 2008; Yao et al., 2010b; Masoudi et al., 2014). In addition, neurons exposed to toxins may appear dark, rounded and/or small, exhibit neuritic blebbing (Figure 2e), and lose GFP expression (Nass et al., 2002; Berkowitz et al., 2008; Pu and Le, 2008; VanDuyn et al., 2010; Ali and Rajini, 2012; Fu et al., 2014a; Masoudi et al., 2014). Selective degeneration can be scored based on any of these morphological changes or the absence of the neurons. In addition, C. elegans dopaminergic neurons that express human α-synuclein degenerate by mid-life (Hamamichi et al., 2008). In contrast, most genetic mouse models of α-synuclein fail to show degeneration of dopamine neurons (Blesa et al., 2012a; Blesa and Przedborski, 2014).

FIGURE 2
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Figure 2. Representative images of the head regions of day-5 adults of strain BZ555 ([dat-1p::GFP]), maintained at 22°C. The images show (a) six healthy dopaminergic neurons (four CEPs [white arrows] and two ADEs [yellow arrows]), (b) two intact cell processes or dendrites (white arrows) of the four CEP neurons, which extend from the pharynx to the tip of the nose (c) the shrinkage of a cell body (white arrow), (d) neuritic blebbing (white arrows), and (e) abrupt gaps or breaks in the dendrites or cell processes (white arrows) caused by 50 mM 6-OHDA. (Scale bars, 50 μm; magnification, 50×. Original image taken by the authors for this paper on a Zeiss LSM 510 laser scanning confocal microscope).

Dopamine Content

Dopamine reuptake transporters (DAT-1 in C. elegans) play a crucial role in the uptake of environmental toxins such as 6-OHDA and MPTP, which enter neurons, cause cell degeneration, and decrease the levels of endogenous dopamine (Gainetdinov et al., 1997; Nass et al., 2002; Pu and Le, 2008; Ali and Rajini, 2012; Masoudi et al., 2014). The dopamine content in C. elegans treated with a neurotoxin can be measured by reverse phase high performance liquid chromatography (RP-HPLC) with electrochemical detection (Pehek et al., 2005; Yao et al., 2010b; Satapathy et al., 2016). Reduced levels of dopamine and the resulting behavioral deficits are found in C. elegans overexpressing LRRK2 (both wild-type and mutated forms; Yao et al., 2010b). LRRK2 animals have a 50–72% reduction in dopamine levels compared to the wild-type control strain N2 (Yao et al., 2010b).

An alternative method is to measure dopamine content using HPLC followed by the detection of chemiluminiscence (Kuwahara et al., 2006; Tsunoda, 2006; Fu et al., 2014a). Post separation, colorimetric oxidation, fluorescence derivatization with ethylenediamine, and peroxyoxalate chemiluminiscence reaction detection are then performed on the extracts containing dopamine and its metabolites (Tsunoda, 2006). This method is highly sensitive, with detection limits in the fentomolar range, and makes it possible to measure dopamine in small-volume samples. HPLC with chemiluminiscence was used to show reduced dopamine levels and a reduced locomotory phenotype in transgenic C. elegans strains expressing A30P or A53T mutant α-synuclein in dopamine neurons (Kuwahara et al., 2006). In another study, the same technique revealed that the dopamine content of 6-OHDA-treated animals was 64% less than untreated controls (Fu et al., 2014a). Interestingly, the levels of dopamine in 6-OHDA-treated animals are elevated after treatment with the natural compound n-butylidenephthalide (Fu et al., 2014a). Additionally, using HPLC with UV detection, Ali and Rajini showed that the dopamine levels of MPTP and organophosphorous insecticide-exposed C. elegans are lower than in untreated controls (Ali and Rajini, 2012).

Lipid Content

Prior research suggests that the aggregation of α-synuclein oligomers is associated with lipid peroxidation due to ROS overload, which can alter cellular membrane composition (Binukumar et al., 2010; Angelova et al., 2015). In C. elegans, intracellular fat droplets can be stained with the fluorescent dye Nile red (a lipophilic stain that fluoresces in a lipid environment), visualized with fluorescence microscopy (Figure 3), and quantified by analyzing the fluorescence staining. Several studies have shown that the NL5901 and OW13 strains have lower Nile red fluorescence than wild-type control N2 animals of the same age, indicating a reduced lipid content in PD strains (Jadiya et al., 2011; Jadiya and Nazir, 2012; Fu et al., 2014a). However, further investigation is warranted to describe the role of lipid content in C. elegans models of PD. For example, the lipid content of PD strains should be directly compared to their corresponding genetic controls, not just to wild-type N2 control strains. In addition, another widely used stain for measuring lipid content in C. elegans, Oil Red O, is a fat-soluble diazo dye that has been widely used to stain lipid droplets in mammalian cells and tissues, and has recently been applied to observing lipid stores in C. elegans (O'Rourke et al., 2009; Elle et al., 2010; Wahlby et al., 2014). This stain measures fat stores contained only in lipid droplets, which correlate well with biochemically-measured lipids (total fatty-acid methyl esters). Whereas Nile red primarily stains acidic lysosome-related gut granules in live or fixed animals (Elle et al., 2010; Wahlby et al., 2014), Oil Red O shows a better correlation with triglyceride levels. Depending on the solvent, Oil Red O can also stain cellular structures in non-adipogenic cell lineages (Elle et al., 2010). Yen and colleagues showed that fixed, but not Nile red-fed (live) wild-type N2 animals reveal fat stores that match label-free coherent anti-Stokes Raman scattering (CARS) imaging or Oil Red O and Nile Red fixed imaging (Yen et al., 2010). Another study by Barros and coworkers compared different methods (Nile red, BODIPY, Sudan Black and Oil Red O) to study the effect of dopamine signaling on fat content in C. elegans. Results showed similarity between fixative based dyes (Sudan Black and Oil Red O) and vital dyes (BODIPY and Nile Red) with smaller measurable decreases for the vital dyes (Barros et al., 2014). It will be interesting to further elucidate the role of lipid content in cellular hallmarks of PD by using these additional tools.

FIGURE 3
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Figure 3. Representative images of Nile red staining of lipid content in live, day-5 adult C. elegans in (a) a wild-type N2 animal under fluorescence microscopy and (b) an OW13 [unc-54p::α-synuclein::YFP + unc-119(+)] animal under fluorescence microscopy. Image (c) depicts an overlay of phase contrast and fluorescence microscopy of a wild-type N2 animal and (d) shows an overlay of phase contrast and fluorescence microscopy of an OW13 animal. Strains were maintained at 22°C. White arrows represent stained fat droplets. Scale bar, 50 μm; magnification, 60x. Original image taken by the authors for this paper on an Olympus FLUORVIEW FV10i confocal microscope.

Behavioral Phenotyping

In humans, movement is controlled by synergistic inputs from the neuronal networks located in the substantia nigra of the ventral midbrain (Groves, 1983). These nerve cells together form an intricate network of axonal processes that synapse with dendritic spines by innervating the basal ganglia (Pickel et al., 1981; Freund et al., 1984). Crosstalk between neurons of the substantia nigra and basal ganglia results in dopamine release, which plays a crucial role in modulating movement (Bernheimer et al., 1973; Lanciego et al., 2012). This modulation is lost in PD due to the loss or degeneration of the dopaminergic neurons in the substantia nigra, which leads to motor dysfunction (Greengard, 2001). In spite of advancements in our understanding of the pathophysiology of PD and the development of several dopamine-based therapies, the exact molecular mechanisms by which dysfunctional dopaminergic systems lead to movement impairments in PD are not fully understood. In addition, dopamine also has been implicated in other functions such as eye movement, motor planning, learning, motivation, and addiction (Wise, 2004; Schultz, 2007). These multiple roles of dopamine in a complicated nervous system pose several questions about its precise role in movement-related disorders like PD. In C. elegans, the dopaminergic system has been well described and found to have structural and functional similarities to that of humans (Duerr et al., 1999; Lee and Ambros, 2001; Nass and Blakely, 2003; Suo et al., 2003; Chase et al., 2004; Chase and Koelle, 2007). In addition, some of the mechanisms of dopamine synthesis, storage, and transport in humans are conserved in C. elegans, and the nerve endings of dopaminergic neurons and synaptic vesicles have similar dopamine levels to those in mammalian neurons (Fuxe and Jonsson, 1973; Bargmann, 1998; Chege and Mccoll, 2014). Studies have established that disrupting dopamine signaling can lead to behavioral phenotypic changes in C. elegans such as altered movement (Omura et al., 2012), defecation (Vidal-Gadea and Pierce-Shimomura, 2012), egg-laying (Weinshenker et al., 1995), food sensing (Sawin et al., 2000), and response to external environmental cues including ethanol and nonanol (Lee et al., 2009; Kimura et al., 2010). In C. elegans, dopamine also controls acclimatization to mechanical stimuli (Sanyal et al., 2004), foraging (Hills et al., 2004), and transitions between crawling and swimming behavior (Vidal-Gadea et al., 2011).

Basal Slowing or Food-Sensing Behavior

The locomotion rates of C. elegans change in the presence or absence of food, and feeding status. For example, well-fed, wild-type animals move more slowly in the presence of bacteria versus when there is no bacterial food source on the petri dish. This foraging behavior is dependent on dopaminergic neurons, which mechanically sense the presence and availability of bacterial food by its texture, and when food is present, decrease the animals' locomotion (Sawin et al., 2000). This slowing in response to abundant food in well-fed animals is called basal slowing. Deficits in dopaminergic function are associated with higher locomotion in the presence of food in well-fed animals, as evidenced by their lower basal slowing response (Yao et al., 2010b; Chen et al., 2013). Starved C. elegans slow down more dramatically in the presence of food, a phenomenon referred to as the enhanced slowing response, which ensures that the animals do not leave their newly found food source (Sawin et al., 2000; Rivard et al., 2010). Unlike basal slowing, which is controlled by dopaminergic neurons, the enhanced slowing response is regulated by serotonin (Sawin et al., 2000).

To determine the basal slowing response, animals are washed in buffer (typically M9) and then transferred to NGM plates with or without OP50 bacterial lawns. Basal slowing, which is measured as the frequency of body bends, is then recorded for 20–60 s and analyzed using data acquisition software as follows: (basal slowing = [rate of movement in the absence of food − rate of movement in the presence of food]/rate of movement in the presence of food) (Cooper et al., 2015). Basal slowing or food sensing behavior can also be measured as: (basal slowing = [movement rate of the animals in the presence of bacteria/movement rate in absence of bacteria] × 100) (Kuwahara et al., 2006). The study by Cooper et al. used food-sensing behavior to assess the functional loss of dopamine neurons in C. elegans expressing the familial Parkinson mutant human α-synuclein in dopamine neurons. The results showed that C. elegans expressing either human mutant α-synuclein (A53T) or human mutant LRRK2 (G2019S) exhibited deficits in this dopamine-related behavior (Cooper et al., 2015). This deficiency can be rescued by a mutation in the insulin-IGF1 receptor C. elegans ortholog, daf-2, a key modulator of aging pathways (Kenyon et al., 1993). Interestingly, the overexpression of LRRK2 (both wild-type and G2019S mutated forms) and cat-2 deletion disrupt the age-dependent basal slowing response. This diminished behavior can be rescued by treatment with exogenous dopamine (Yao et al., 2010b; Johnson et al., 2015).

Area-Restricted Searching (ARS) Behavior

Area-restricted searching (ARS) is a foraging behavior in which wild-type animals minimize searching in areas that have abundant food and extend the search to larger areas when food is scarce. As the time since removal from food increases, animals turn less frequently towards the food (Hills et al., 2004; Gray et al., 2005; Chen et al., 2013). This is a goal-directed behavior that involves dopamine signaling. Removing or damaging dopaminergic neurons can lead to abnormal or abolished ARS behavior. For example, ARS behavior was rescued by administering exogenous dopamine to animals with defective dopamine signaling (Hills et al., 2004). ARS can be measured by transferring well-fed animals to NGM plates and videotaping them for 60 s after 5 and 30 min. The number of turns that exceed 90 degrees are counted from the tracks of each animal at each time-point (Cooper et al., 2015). ARS is impaired in both α-synuclein and LRRK2 PD mutants (Cooper et al., 2015). Daf-2 mutations increase searching in both PD strains, suggesting a role for aging in modulating dopamine-dependent behaviors in nematode models of PD (Cooper et al., 2015).

Chemotaxis Assay

Caenorhabditis elegans can sense and respond to a multitude of environmental cues. These responses can be both aversive and attractive (Bargmann, 2006). For example, under standard laboratory culturing conditions, untreated wild-type (N2) animals avoid ethanol. However, when these animals are continuously exposed to ethanol, they develop a tolerance to and preference for ethanol, a response which is controlled by the dopamine system (Davies et al., 2004; Lee et al., 2009). Unlike wild-type animals, cat-2 and tph-1 mutants lacking a functional dopamine system do not develop an ethanol preference to chronic ethanol exposure (Lee et al., 2009). Ethanol avoidance is significantly decreased in non-ethanol-pretreated animals that express human mutant α-synuclein and mutant LRRK2 compared to those expressing wild-type α-synuclein and wild-type LRRK2 (Cooper et al., 2015). Interestingly, ethanol avoidance is restored in an α-synuclein mutant with a deletion of the daf-2 gene, indicating that slowing aging also slows PD symptoms. To assay ethanol preference as a surrogate measure of the dopamine system, animals are incubated on an ethanol plate and transferred to assay plates that are divided into equal quadrants. Ethanol is provided in two quadrants, and animals are allowed to move freely for 30 min; the time preference for the quadrants is scored during this time. A preference index (PI) is calculated as ([number of animals in the ethanol quadrants]–[number of animals in control quadrants])/the total number of animals tested (Lee et al., 2009). This assay could also be used to assess the PI of PD animals with an impaired dopaminergic system caused by chemical exposure.

In C. elegans, the response to the aversive odorant nonanol is regulated by dopamine signaling (Bargmann, 2006; Kimura et al., 2010; Fatima et al., 2014; Sashidhara et al., 2014; Satapathy et al., 2016). When a drop of nonanol is placed near the head of a wild-type worm, the worm senses it and moves away as a chemotactic “aversive” response. However, when its dopamine content is diminished, the animals take longer to respond to the chemical stimulus. The response time to nonanol is increased 2-fold in the α-synuclein overexpressing strain NL5901 after treatment with ida-1 (ortholog of mammalian diabetes autoantigen IA-2) RNAi (Fatima et al., 2014). In contrast, certain botanical compounds have shown to reduce the time required by both wild-type (N2 exposed to 6-OHDA/pesticide) and α-synuclein overexpressing strains (NL5901) to respond to nonanol (Sashidhara et al., 2014; Satapathy et al., 2016). This suggests that the “nonanol repulsion assay” can be used as an indirect measure of dopamine content in nematodes with impaired dopamine signaling.

Swim to Crawl Transition

Gait can be defined as alterations in the patterns of movement based on the environment currently occupied by an animal. In humans, the basal ganglia regulate motor movement during gait, which activates dopaminergic neurons (Marsden, 1982; Mink and Thach, 1991; Fukuyama et al., 1997; Koepp et al., 1998). In PD, dysfunction in the basal ganglia region contributes to impaired gait functions and rhythms (Morris et al., 1996; Hausdorff et al., 1998; Sofuwa et al., 2005). Gaits in C. elegans are mainly characterized as crawling (on solid “agar” media) and swimming (in liquid media) (White et al., 1986; Pierce-Shimomura et al., 2008). On agar, nematodes move or crawl in a classical sinusoidal fashion. This changes to “thrashing” or swimming when the animals are moved to liquid media. The mechanisms behind this gait transition are unknown; however, roles for bioamine neurotransmitters such as dopamine and serotonin have been implicated (Mesce and Pierce-Shimomura, 2010).

In C. elegans, dopamine is responsible for a wide array of behaviors including the gait transition from swim to crawl (Vidal-Gadea et al., 2011). The activation of dopamine neurons by optogenetics confirmed that the switch from crawling to swimming involves signaling through D1-like dopamine receptors, which is similar to the pattern the animals exhibit when they crawl off the bacterial food source (Sawin et al., 2000; Vidal-Gadea et al., 2011). Under both conditions, dopamine functions by decreasing the speed of the animal's movement. Animals with impaired dopaminergic signaling can exhibit opposing behavioral phenotypes, and the genetic ablation of all dopaminergic neurons can impair the transitions between swimming and crawling and lead to paralysis in animals due to incessant swimming (the swimming-induced paralysis or SWIP phenotype; Vidal-Gadea et al., 2011). The dopamine transporter DAT-1 plays an important role in dopamine reuptake and clearance. In animals that exert maximal physical activity during swimming, mutations in DAT-1 lead to SWIP (McDonald et al., 2007). In humans, PD is characterized by impaired gait and the failure to transition between locomotory patterns (Jankovic, 2008). The failure of C. elegans to transition between swimming and crawling when the dopamine system is impaired reinforces the validity of C. elegans PD models.

A swim-to-crawl assay involves growing animals on NGM plates seeded with OP50 bacteria and then changing the environmental conditions to affect movement. Such changes could include increasing or decreasing the viscosity of the medium or providing mechanical stimulation with magnetic particles, as described by Vidal-Gadea et al. (2011). Gait transitions are evaluated by video recording movement before and after altering the conditions. For swim-to-crawl transition, C. elegans lacking dopaminergic neurons will exhibit truncated movement upon transitioning from a liquid to an agar medium. Similarly, animals lacking the DAT-1 receptor accumulate high amounts of endogenous dopamine, which induces a switch from the swim to crawl phenotype before causing the SWIP phenotype (McDonald et al., 2007; Vidal-Gadea et al., 2011). In C. elegans, the swim-to-crawl assay has been used to demonstrate that the membrane protein tetraspanin (TSP-17) protects dopaminergic neurons against 6-OHDA-mediated neurodegeneration and the toxicity caused by increased concentrations of endogenous intracellular dopamine (Masoudi et al., 2014).

Mechanosensory Responses

Previous studies in C. elegans indicate that dopaminergic neurons are mechanosensory (Loer and Kenyon, 1993; Liu and Sternberg, 1995; Duerr et al., 1999; Sawin et al., 2000; Bettinger and McIntire, 2004; Hills et al., 2004; Sanyal et al., 2004; Abdelhack, 2016). Dopaminergic neurons respond to anterior touch stimulation (Sanders et al., 2013). Caenorhabditis elegans lacking tyrosine hydroxylase (cat-2 mutants) display defective food-sensing behavior because they fail to slow down when they encounter a bacterial food source. This basal slowing response is mediated by dopamine signaling and depends on physically touching the bacterial food source (Sawin et al., 2000). Such interactions between dopamine and mechanosensory touch responses are not well understood. Nevertheless, these interactions appear to be necessary for regulating foraging in nematodes (Sawin et al., 2000). This confirms a role for dopamine in modulating the response to a non-localized mechanical stimulus (such as taps) administered to the NGM plate (Sanyal et al., 2004). Animals respond to external tapping by escalating their forward or backward motion. Repeated tapping attenuates the reversal frequencies and leads to habituation (Rose and Rankin, 2001). The time required to respond to the tap can be used as a measure of dopaminergic function as the loss of dopaminergic function can alter this behavior (Sanyal et al., 2004). Although this behavior has not yet been studied in animals with Parkinson's-like symptoms, mechanosensory touch responses have been studied in C. elegans neurodegenerative models of Huntington's disease, Alzheimer's disease, and tauopathies (Parker et al., 2001; Miyasaka et al., 2005; Gordon et al., 2008). Therefore, this behavior can be used to assess healthy/impaired dopaminergic function in wild-type and PD animals using cat-2 mutants as a negative control, since these mutants habituate to tapping faster than wild-type strains (Chen et al., 2013).

Dauer-Dependent Behavior

Under favorable conditions, the life cycle of C. elegans includes the egg stage, four larval stages (L1-L4), and an adult stage, which is reproductive in hermaphrodites and lasts for 3–5 days. When exposed to overcrowded conditions, limited food, or chemical or physical stressors, animals enter an alternative stage after L2 known as dauer diapause (Cassada and Russell, 1975; Fielenbach and Antebi, 2008). The entry to dauer is regulated by daf-16 (forkhead box O or FOXO) and its upstream regulator daf-2 (insulin receptor), which are important modulators of aging and lifespan (Kenyon et al., 1993; Lee et al., 2001). Although this behavior occurs independent of dopamine signaling, once the animals enter the arrest phase they respond to any changes in dopamine signaling by increasing their body movement (Gaglia and Kenyon, 2009). Therefore, dauer movement assays can be used to assess this behavioral change. For example, dauer formation can be induced by exposing djr-1.2 mutants to the heavy metal Mn, transferring them to NGM plates without bacterial food, and storing for 72 h (Chen P. et al., 2015). The dauer diapause can then be determined using body movements which is defined as one complete body bend in forward or backwards direction in a 1 min duration (Gaglia and Kenyon, 2009; Chen P. et al., 2015). The cat-2 deletion mutants that have diminished DA signaling are used as a positive control. Both djr-1.2 and cat-2 mutants exhibit increased dauer movement compared with controls. When exposed to Mn, the djr-1.2 mutants show a further increase in movement compared with untreated controls, indicating reduced dopamine signaling (Chen P. et al., 2015). However, this behavior can be rescued by the overexpression of DAF-16. This behavioral assay was also important for assessing the interactions between aging, a PD environmental risk factor (i.e., Mn), and the PD-associated homolog DJ-1 (Chen P. et al., 2015).

Fecundity

Fecundity is an important assay for determining the egg-laying behavior of C. elegans and is controlled by dopamine (Schafer and Kenyon, 1995; Weinshenker et al., 1995). The exposure to environmental toxins can lead to changes in dopamine signaling, which in turn can alter fecundity or brood size in C. elegans (VanDuyn et al., 2010). Fecundity can be measured by performing progeny count assays. Age-synchronous adults are placed on individual plates each day until they cease reproducing. The number of eggs or viable progeny is then counted. When the assays are performed by counting progeny, the plates are incubated at a specific temperature and the eggs are allowed to develop for 48 h before the brood size is determined (Hodgkin and Barnes, 1991; Scerbak et al., 2016). The assessment of brood size or total progeny has been performed in neurotoxin-treated (6-OHDA and insecticide) models (Satapathy et al., 2016) and in different PD mutants (Cooper et al., 2015) of C. elegans. LRRK2 mutants have decreased fecundity due to decreased levels of DA, and this decrease cannot not be rescued by the daf-2 mutation (Yao et al., 2010b; Cooper et al., 2015). Also, a significant decrease in brood size (25–31%) occurs in animals exposed to 6-OHDA, which can be slightly increased by curcumin treatment (Satapathy et al., 2016). Overall, fecundity can be used to measure healthspan in wild-type and PD animals to assess the effects of experimental treatments on the overall pathology and behavioral phenotypes of C. elegans.

Rate of Defecation

In C. elegans, defecation is a behavior controlled by a series of muscle contractions, i.e., a motor program that occurs in the intestinal “enteric” muscles of the animals. On average, it occurs every 50 s (Dal Santo et al., 1999) and this cycle remains constant at 20°C. Dopamine has been implicated in controlling the defecation cycle (Weinshenker et al., 1995; McDonald et al., 2006; Vidal-Gadea and Pierce-Shimomura, 2012). Previous studies have demonstrated that excess dopamine reduces the defecation rate by decreasing expulsion muscle contractions (Weinshenker et al., 1995). Defecation is carried out in three steps: posterior body muscle contraction (pBoc), anterior body muscle contraction (aBoc), and expulsion muscle contraction (Branicky et al., 2001; Kwan et al., 2008). The length of the defecation cycle can be determined by viewing animals with a dissecting microscope and measuring the duration between two consecutive pBoc contractions in adult animals at 20°C or as specified (Branicky et al., 2001; Cooper et al., 2015). A recent study showed slower rates of defecation in α-synuclein and LRRK2 mutants compared to normal rates in cat-2 mutants, suggesting that defecation behavior occurs independent of dopamine in these PD models (Cooper et al., 2015). However, cat-2 mutants may not completely lack dopamine (Sanyal et al., 2004). The rate of defecation should be further investigated as an indicator of physiological outcome in PD animals.

Locomotion

In C. elegans, locomotion or motility is a useful marker to assess healthspan (Bansal et al., 2015). The dorsal and ventral muscles coordinate to control the classical sinusoidal locomotion patterns in nematodes (Croll, 1975; Donnelly et al., 2013). Motility can be assessed in aged individuals using an A-B-C class-based system (Herndon et al., 2002). Class A represents a normal sinusoidal pattern, class B represents spontaneous reversals or induced motion with gentle prodding, and class C represents no movement or only movement of the head in response to gentle prodding. These patterns are also influenced by the presence or absence of food and exposure to mechanical or chemical stimuli (Omura et al., 2012). Studies have shown that disrupting DA signaling using genetic mutations or exposure to environmental toxins (6-OHDA or MPTP) can change the locomotory behavior of C. elegans (Ali and Rajini, 2012; Cooper et al., 2015; Liu et al., 2015). Such altered behavior can be assessed by observing changes in the typical sinusoidal pattern, including irregular body bends or thrashing behavior. Body bends are counted as one muscle contraction that leads to a complete bend of the dorsal or ventral side of the animal (Ghosh and Emmons, 2008). The term “thrashing” is used to define motility when nematodes are placed in a drop of liquid (e.g. M9 buffer), and it is determined by measuring the frequency of lateral movements or the direction of mid-body bending (Buckingham and Sattelle, 2009). Locomotory behavior can be quantified by viewing or recording worm movements through a stereomicroscope. Numerous automated programs facilitate the analysis of digitally recorded data, including Worm Tracker 2.0, OptoTracker, The Parallel Worm Tracker, Nemo, Multimodal illumination and tracking system, the Multi Worm Tracker, and CoLBeRT (Husson et al., 2013). Recently, a microfluidic device was also used to measure the locomotion of C. elegans using an electric signal (Jung et al., 2016).

Conclusions

Well-developed imaging techniques and genetic malleability make C. elegans a useful model for testing compounds to treat the cellular and related behavioral symptoms of PD and investigating the basic molecular mechanisms underlying potential therapeutic approaches. The pathological and behavioral markers discussed in this review could be useful for performing screening experiments and establishing crucial connections between PD-like pathology, possible susceptibility factors, and the mechanisms triggered by exposure to novel drug molecules.

Author Contributions

MM and SM contributed equally to the concept, background research, and writing of the manuscript. EMV contributed to the background research, writing and editing of the manuscript. All authors made intellectual contributions, edited, and approved the manuscript for publication.

Funding

This research was funded by grants from the National Institute of General Medical Sciences of the National Institutes of Health (1) under an Institutional Development Award (IDeA; grant number P20GM103395) and (2) under a Building Infrastructure Leading to Diversity Award (BUILD; three linked grants numbered RL5GM118990, TL4 GM118992, and 1UL1GM118991). The work is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. We thank the office of the Vice Chancellor of Research, Dr. Larry Hinzman, for funding associated with the publication costs of this article.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

The authors thank Mitchell Reed for his help with confocal microscopy.

References

Abdelhack, M. (2016). Dopaminergic neurons modulate locomotion in Caenorhabditis elegans. bioRxiv. doi: 10.1101/056192

CrossRef Full Text | Google Scholar

Alegre-Abarrategui, J., Christian, H., Lufino, M. M., Mutihac, R., Venda, L. L., Ansorge, O., et al. (2009). LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum. Mol. Genet. 18, 4022–4034. doi: 10.1093/hmg/ddp346

PubMed Abstract | CrossRef Full Text | Google Scholar

Ali, S. J., and Rajini, P. S. (2012). Elicitation of dopaminergic features of Parkinson's disease in C. elegans by monocrotophos, an organophosphorous insecticide. CNS Neurol. Disord. Drug Targets 11, 993–1000. doi: 10.2174/1871527311211080008

PubMed Abstract | CrossRef Full Text | Google Scholar

Angelova, P. R., Horrocks, M. H., Klenerman, D., Gandhi, S., Abramov, A. Y., and Shchepinov, M. S. (2015). Lipid peroxidation is essential for α-synuclein-induced cell death. J. Neurochem. 133, 582–589. doi: 10.1111/jnc.13024

PubMed Abstract | CrossRef Full Text | Google Scholar

Ariga, H., Takahashi-Niki, K., Kato, I., Maita, H., Niki, T., and Iguchi-Ariga, S. M. (2013). Neuroprotective function of DJ-1 in Parkinson's disease. Oxid. Med. Cell. Longev. 2013:683920. doi: 10.1155/2013/683920

PubMed Abstract | CrossRef Full Text | Google Scholar

Aschner, M., and Aschner, J. L. (1991). Manganese neurotoxicity: cellular effects and blood-brain barrier transport. Neurosci. Biobehav. Rev. 15, 333–340. doi: 10.1016/S0149-7634(05)80026-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Aschner, M., Erikson, K. M., Herrero Hernandez, E., and Tjalkens, R. (2009). Manganese and its role in Parkinson's disease: from transport to neuropathology. Neuromol. Med. 11, 252–266. doi: 10.1007/s12017-009-8083-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Asthana, J., Mishra, B. N., and Pandey, R. (2016). Acacetin promotes healthy aging by altering stress response in Caenorhabditis elegans. Free Radic. Res. 50, 861–874. doi: 10.1080/10715762.2016.1187268

PubMed Abstract | CrossRef Full Text | Google Scholar

Bansal, A., Zhu, L. J., Yen, K., and Tissenbaum, H. A. (2015). Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc. Natl. Acad. Sci. U.S.A. 112, E277–E286. doi: 10.1073/pnas.1412192112

PubMed Abstract | CrossRef Full Text | Google Scholar

Bargmann, C. I. (1998). Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033. doi: 10.1126/science.282.5396.2028

PubMed Abstract | CrossRef Full Text | Google Scholar

Bargmann, C. I. (2006). Chemosensation in C. elegans. WormBook, 1–29. doi: 10.1895/wormbook.1.123.1

CrossRef Full Text

Barros, A. G. D. A., Bridi, J. C., De Souza, B. R., De Castro Júnior, C., De Lima Torres, K. C., Malard, L., et al. (2014). Dopamine signaling regulates fat content through b-oxidation in Caenorhabditis elegans. PLoS ONE 9:e85874. doi: 10.1371/journal.pone.0085874

CrossRef Full Text | Google Scholar

Beitz, J. M. (2014). Parkinson's disease: a review. Front. Biosci. 6, 65–74. doi: 10.2741/S415

PubMed Abstract | CrossRef Full Text | Google Scholar

Benedetto, A., Au, C., Avila, D. S., Milatovic, D., and Aschner, M. (2010). Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans. PLoS Genet. 6:e1001084. doi: 10.1371/journal.pgen.1001084

PubMed Abstract | CrossRef Full Text | Google Scholar

Berkowitz, L. A., Hamamichi, S., Knight, A. L., Harrington, A. J., Caldwell, G. A., and Caldwell, K. A. (2008). Application of a C. elegans dopamine neuron degeneration assay for the validation of potential Parkinson's disease genes. J. Vis. Exp. pii:835. doi: 10.3791/835

PubMed Abstract | CrossRef Full Text | Google Scholar

Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K., and Seitelberger, F. (1973). Brain dopamine and the syndromes of Parkinson and Huntington Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 20, 415–455. doi: 10.1016/0022-510X(73)90175-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Bethlem, J., and Den Hartog Jager, W. A. (1960). The incidence and characteristics of Lewy bodies in idiopathic paralysis agitans (Parkinson's disease). J. Neurol. Neurosurg. Psychiatr. 23, 74–80. doi: 10.1136/jnnp.23.1.74

PubMed Abstract | CrossRef Full Text | Google Scholar

Bettinger, J. C., and McIntire, S. L. (2004). State-dependency in C. elegans. Genes Brain Behav. 3, 266–272. doi: 10.1111/j.1601-183X.2004.00080.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Binukumar, B. K., Bal, A., Kandimalla, R. J. L., and Gill, K. D. (2010). Nigrostriatal neuronal death following chronic dichlorvos exposure: crosstalk between mitochondrial impairments, alpha synuclein aggregation, oxidative damage and behavioral changes. Mol. Brain 3:35. doi: 10.1186/1756-6606-3-35

PubMed Abstract | CrossRef Full Text | Google Scholar

Biskup, S., Moore, D. J., Celsi, F., Higashi, S., West, A. B., Andrabi, S. A., et al. (2006). Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann. Neurol. 60, 557–569. doi: 10.1002/ana.21019

PubMed Abstract | CrossRef Full Text | Google Scholar

Blandini, F., and Armentero, M. T. (2012). Animal models of Parkinson's disease. FEBS J. 279, 1156–1166. doi: 10.1111/j.1742-4658.2012.08491.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Blesa, J., Phani, S., Jackson-Lewis, V., and Przedborski, S. (2012a). Classic and new animal models of Parkinson's disease. J. Biomed. Biotechnol. 2012:845618. doi: 10.1155/2012/845618

PubMed Abstract | CrossRef Full Text | Google Scholar

Blesa, J., Pifl, C., Sánchez-González, M. A., Juri, C., García-Cabezas, M. A., Adánez, R., et al. (2012b). The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study. Neurobiol. Dis. 48, 79–91. doi: 10.1016/j.nbd.2012.05.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Blesa, J., and Przedborski, S. (2014). Parkinson's disease: animal models and dopaminergic cell vulnerability. Front. Neuroanat. 8:155. doi: 10.3389/fnana.2014.00155

PubMed Abstract | CrossRef Full Text | Google Scholar

Bodhicharla, R., Nagarajan, A., Winter, J., Adenle, A., Nazir, A., Brady, D., et al. (2012). Effects of α-synuclein overexpression in transgenic Caenorhabditis elegans Strains. CNS Neurol. Disord. Drug Targets 11, 965–975. doi: 10.2174/1871527311211080005

PubMed Abstract | CrossRef Full Text | Google Scholar

Bonifati, V., Rizzu, P., Van Baren, M. J., Schaap, O., Breedveld, G. J., Krieger, E., et al. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259. doi: 10.1126/science.1077209

PubMed Abstract | CrossRef Full Text | Google Scholar

Bove, J., Prou, D., Perier, C., and Przedborski, S. (2005). Toxin-induced models of Parkinson's disease. NeuroRx 2, 484–494. doi: 10.1602/neurorx.2.3.484

PubMed Abstract | CrossRef Full Text | Google Scholar

Branicky, R., Shibata, Y., Feng, J. L., and Hekimi, S. (2001). Phenotypic and suppressor analysis of defecation in clk-1 mutants reveals that reaction to changes in temperature is an active process in Caenorhabditis elegans. Genetics 159, 997–1006.

PubMed Abstract | Google Scholar

Braungart, E., Gerlach, M., Riederer, P., Baumeister, R., and Hoener, M. C. (2004). Caenorhabditis elegans MPP+ model of Parkinson's disease for high-throughput drug screenings. Neurodegener. Dis. 1, 175–183. doi: 10.1159/000080983

PubMed Abstract | CrossRef Full Text | Google Scholar

Buckingham, S. D., and Sattelle, D. B. (2009). Fast, automated measurement of nematode swimming (thrashing) without morphometry. BMC Neurosci. 10:84. doi: 10.1186/1471-2202-10-84

PubMed Abstract | CrossRef Full Text | Google Scholar

Buttner, S., Broeskamp, F., Sommer, C., Markaki, M., Habernig, L., Alavian-Ghavanini, A., et al. (2014). Spermidine protects against alpha-synuclein neurotoxicity. Cell Cycle 13, 3903–3908. doi: 10.4161/15384101.2014.973309

PubMed Abstract | CrossRef Full Text | Google Scholar

Calamini, B., Silva, M. C., Madoux, F., Hutt, D. M., Khanna, S., Chalfant, M. A., et al. (2011). Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8, 185–196. doi: 10.1038/nchembio.763

PubMed Abstract | CrossRef Full Text | Google Scholar

Caldwell, G. A., and Caldwell, K. A. (2008). Traversing a wormhole to combat Parkinson's disease. Dis. Model. Mech. 1, 32–36. doi: 10.1242/dmm.000257

PubMed Abstract | CrossRef Full Text | Google Scholar

Calne, D. B., Chu, N. S., Huang, C. C., Lu, C. S., and Olanow, W. (1994). Manganism and idiopathic parkinsonism: similarities and differences. Neurology 44, 1583–1586. doi: 10.1212/WNL.44.9.1583

PubMed Abstract | CrossRef Full Text | Google Scholar

Cao, S., Gelwix, C. C., Caldwell, K. A., and Caldwell, G. A. (2005). Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J. Neurosci. 25, 3801–3812. doi: 10.1523/JNEUROSCI.5157-04.2005

PubMed Abstract | CrossRef Full Text | Google Scholar

Cassada, R. C., and Russell, R. L. (1975). The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev. Biol. 46, 326–342. doi: 10.1016/0012-1606(75)90109-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Chakraborty, S., Bornhorst, J., Nguyen, T. T., and Aschner, M. (2013). Oxidative stress mechanisms underlying Parkinson's disease-associated neurodegeneration in C. elegans. Int. J. Mol. Sci. 14, 23103–23128. doi: 10.3390/ijms141123103

PubMed Abstract | CrossRef Full Text | Google Scholar

Chase, D. L., and Koelle, M. R (2007). Biogenic amine neurotransmitters in C. elegans. WormBook, 1–15. doi: 10.1895/wormbook.1.132.1. Available online at: https://www.researchgate.net/publication/5796589_Biogenic_amine_neurotransmitters_in_C_elegans

PubMed Abstract | CrossRef Full Text | Google Scholar

Chase, D. L., Pepper, J. S., and Koelle, M. R. (2004). Mechanism of extrasynaptic dopamine signaling in Caenorhabditis elegans. Nat. Neurosci. 7, 1096–1103. doi: 10.1038/nn1316

PubMed Abstract | CrossRef Full Text | Google Scholar

Chege, P. M., and Mccoll, G. (2014). Caenorhabditis elegans: a model to investigate oxidative stress and metal dyshomeostasis in Parkinson's disease. Front. Aging Neurosci. 6:89. doi: 10.3389/fnagi.2014.00089

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, P., Dewitt, M. R., Bornhorst, J., Soares, F. A., Mukhopadhyay, S., Bowman, A. B., et al. (2015). Age- and manganese-dependent modulation of dopaminergic phenotypes in a C-elegans DJ-1 genetic model of Parkinson's disease. Metallomics 7, 289–298. doi: 10.1039/C4MT00292J

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, P., Martinez-Finley, E. J., Bornhorst, J., Chakraborty, S., and Aschner, M. (2013). Metal-induced neurodegeneration in C. elegans. Front. Aging Neurosci. 5:18. doi: 10.3389/fnagi.2013.00018

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, Y. M., Liu, S. P., Lin, H. L., Chan, M. C., Chen, Y. C., Huang, Y. L., et al. (2015). Irisflorentin improves alpha-synuclein accumulation and attenuates 6-OHDA-induced dopaminergic neuron degeneration, implication for Parkinson's disease therapy. Biomedicine (Taipei) 5:4. doi: 10.7603/s40681-015-0004-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Choi, J., Sullards, M. C., Olzmann, J. A., Rees, H. D., Weintraub, S. T., Bostwick, D. E., et al. (2006). Oxidative Damage of DJ-1 Is Linked to Sporadic Parkinson and Alzheimer Diseases. J. Biol. Chem. 281, 10816–10824. doi: 10.1074/jbc.M509079200

PubMed Abstract | CrossRef Full Text | Google Scholar

Consortium, T. C. E. S. (1998). Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018. doi: 10.1126/science.282.5396.2012

PubMed Abstract | CrossRef Full Text

Cooper, J. F., Dues, D. J., Spielbauer, K. K., Machiela, E., Senchuk, M. M., and Van Raamsdonk, J. M. (2015). Delaying aging is neuroprotective in Parkinson's disease: a genetic analysis in C. elegans models. npj Parkinson Dis. 1:15022. doi: 10.1038/npjparkd.2015.22

CrossRef Full Text | Google Scholar

Croll, N. A. (1975). Behavioural analysis of nematode movement. Adv. Parasitol. 13, 71–122. doi: 10.1016/S0065-308X(08)60319-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Dal Santo, P., Logan, M. A., Chisholm, A. D., and Jorgensen, E. M. (1999). The inositol trisphosphate receptor regulates a 50-second behavioral rhythm in C-elegans. Cell 98, 757–767. doi: 10.1016/S0092-8674(00)81510-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Davies, A. G., Bettinger, J. C., Thiele, T. R., Judy, M. E., and Mcintire, S. L. (2004). Natural variation in the npr-1 gene modifies ethanol responses of wild strains of C. elegans. Neuron 42, 731–743. doi: 10.1016/j.neuron.2004.05.004

PubMed Abstract | CrossRef Full Text | Google Scholar

David, D. C., Ollikainen, N., Trinidad, J. C., Cary, M. P., Burlingame, A. L., and Kenyon, C. (2010). Widespread Protein Aggregation as an Inherent Part of Aging in C. elegans. PLoS Biol. 8:e1000450. doi: 10.1371/journal.pbio.1000450

PubMed Abstract | CrossRef Full Text | Google Scholar

Dawson, T. M., and Dawson, V. L. (2003). Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819–822. doi: 10.1126/science.1087753

PubMed Abstract | CrossRef Full Text | Google Scholar

Dawson, T. M., Ko, H. S., and Dawson, V. L. (2010). Genetic animal models of Parkinson's disease. Neuron 66, 646–661. doi: 10.1016/j.neuron.2010.04.034

PubMed Abstract | CrossRef Full Text | Google Scholar

Dexter, P. M., Caldwell, K. A., and Caldwell, G. A. (2012). A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders. Neurotherapeutics 9, 393–404. doi: 10.1007/s13311-012-0109-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Dias, V., Junn, E., and Mouradian, M. M. (2013). The role of oxidative stress in parkinson's disease. J. Parkinson's Dis. 3, 461–491. doi: 10.3233/JPD-130230

PubMed Abstract | CrossRef Full Text | Google Scholar

Dickson, D. W. (2012). Parkinson's disease and parkinsonism: neuropathology. Cold Spring Harb. Perspect. Med. 2:a009258. doi: 10.1101/cshperspect.a009258

PubMed Abstract | CrossRef Full Text | Google Scholar

Donnelly, J. L., Clark, C. M., Leifer, A. M., Pirri, J. K., Haburcak, M., Francis, M. M., et al. (2013). Monoaminergic orchestration of motor programs in a complex C. elegans behavior. PLoS Biol. 11:e1001529. doi: 10.1371/journal.pbio.1001529

PubMed Abstract | CrossRef Full Text | Google Scholar

Doty, R. L. (2012). Olfactory dysfunction in Parkinson disease. Nat. Rev. Neurol. 8, 329–339. doi: 10.1038/nrneurol.2012.80

PubMed Abstract | CrossRef Full Text | Google Scholar

Duerr, J. S., Frisby, D. L., Gaskin, J., Duke, A., Asermely, K., Huddleston, D., et al. (1999). The cat-1 gene of Caenorhabditis elegans encodes a vesicular monoamine transporter required for specific monoamine-dependent behaviors. J. Neurosci. 19, 72–84.

PubMed Abstract | Google Scholar

Edwards, C., Canfield, J., Copes, N., Brito, A., Rehan, M., Lipps, D., et al. (2015). Mechanisms of amino acid-mediated lifespan extension in Caenorhabditis elegans. BMC Genet. 16:8. doi: 10.1186/s12863-015-0167-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Elle, I. C., Olsen, L. C., Pultz, D., Rodkaer, S. V., and Faergeman, N. J. (2010). Something worth dyeing for: molecular tools for the dissection of lipid metabolism in Caenorhabditis elegans. FEBS Lett. 584, 2183–2193. doi: 10.1016/j.febslet.2010.03.046

PubMed Abstract | CrossRef Full Text | Google Scholar

Esposito, G., Ana Clara, F., and Verstreken, P. (2012). Synaptic vesicle trafficking and Parkinson's disease. Dev. Neurobiol. 72, 134–144. doi: 10.1002/dneu.20916

PubMed Abstract | CrossRef Full Text | Google Scholar

Fatima, S., Haque, R., Jadiya, P., Shamsuzzama Kumar, L., and Nazir, A. (2014). Ida-1, the Caenorhabditis elegans Orthologue of Mammalian Diabetes Autoantigen IA-2, Potentially Acts as a Common Modulator between Parkinson's Disease and Diabetes: role of Daf-2/Daf-16 Insulin Like Signalling Pathway. PLoS ONE 9:113986. doi: 10.1371/journal.pone.0113986

PubMed Abstract | CrossRef Full Text | Google Scholar

Fielenbach, N., and Antebi, A. (2008). C. elegans dauer formation and the molecular basis of plasticity. Genes Dev. 22, 2149–2165. doi: 10.1101/gad.1701508

PubMed Abstract | CrossRef Full Text | Google Scholar

Fire, A., Xu, S., Montgomery, M. K., Kostas, S. A., Driver, S. E., and Mello, C. C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811. doi: 10.1038/35888

PubMed Abstract | CrossRef Full Text | Google Scholar

Fitsanakis, V. A. (2012). Caenorhabditis elegans: an emerging model system for pesticide neurotoxicity. J. Environ. Anal. Toxicol. S4:003. doi: 10.4172/2161-0525.S4-003

CrossRef Full Text

Fleming, L., Mann, J. B., Bean, J., Briggle, T., and Sanchez-Ramos, J. R. (1994). Parkinson's disease and brain levels of organochlorine pesticides. Ann. Neurol 36, 100–103. doi: 10.1002/ana.410360119

PubMed Abstract | CrossRef Full Text | Google Scholar

Fleming, S. M., and Chesselet, M. F. (2006). Behavioral phenotypes and pharmacology in genetic mouse models of Parkinsonism. Behav. Pharmacol. 17, 383–391. doi: 10.1097/00008877-200609000-00004

PubMed Abstract | CrossRef Full Text | Google Scholar

Freund, T. F., Powell, J. F., and Smith, A. D. (1984). Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines. Neuroscience 13, 1189–1215. doi: 10.1016/0306-4522(84)90294-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, R. H., Harn, H. J., Liu, S. P., Chen, C. S., Chang, W. L., Chen, Y. M., et al. (2014a). n-butylidenephthalide protects against dopaminergic neuron degeneration and alpha-synuclein accumulation in Caenorhabditis elegans models of Parkinson's disease. PLoS ONE 9:e85305. doi: 10.1371/journal.pone.0085305

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, R. H., Wang, Y. C., Chen, C. S., Tsai, R. T., Liu, S. P., Chang, W. L., et al. (2014b). Acetylcorynoline attenuates dopaminergic neuron degeneration and alpha-synuclein aggregation in animal models of Parkinson's disease. Neuropharmacology 82, 108–120. doi: 10.1016/j.neuropharm.2013.08.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Fukuyama, H., Ouchi, Y., Matsuzaki, S., Nagahama, Y., Yamauchi, H., Ogawa, M., et al. (1997). Brain functional activity during gait in normal subjects: a SPECT study. Neurosci. Lett. 228, 183–186. doi: 10.1016/S0304-3940(97)00381-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Fuxe, K., and Jonsson, G. (1973). The histochemical fluorescence method for the demonstration of catecholamines. Theory, practice and application. J. Histochem. Cytochem. 21, 293–311. doi: 10.1177/21.4.293

PubMed Abstract | CrossRef Full Text | Google Scholar

Gaglia, M. M., and Kenyon, C. (2009). Stimulation of movement in a quiescent, hibernation-like form of Caenorhabditis elegans by dopamine signaling. J. Neurosci. 29, 7302–7314. doi: 10.1523/JNEUROSCI.3429-08.2009

PubMed Abstract | CrossRef Full Text | Google Scholar

Gainetdinov, R. R., Fumagalli, F., Jones, S. R., and Caron, M. G. (1997). Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter. J. Neurochem. 69, 1322–1325. doi: 10.1046/j.1471-4159.1997.69031322.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Gatto, N. M., Rhodes, S. L., Manthripragada, A. D., Bronstein, J., Cockburn, M., Farrer, M., et al. (2010). Synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease. Neuroepidemiology 35, 191–195. doi: 10.1159/000315157

PubMed Abstract | CrossRef Full Text | Google Scholar

Gegg, M. E., Burke, D., Heales, S. J., Cooper, J. M., Hardy, J., Wood, N. W., et al. (2012). Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann. Neurol. 72, 455–463. doi: 10.1002/ana.23614

PubMed Abstract | CrossRef Full Text | Google Scholar

Ghosh, R., and Emmons, S. W. (2008). Episodic swimming behavior in the nematode C. elegans. J. Exp. Biol. 211, 3703–3711. doi: 10.1242/jeb.023606

PubMed Abstract | CrossRef Full Text | Google Scholar

Gitler, A. D., Chesi, A., Geddie, M. L., Strathearn, K. E., Hamamichi, S., Hill, K. J., et al. (2009). Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41, 308–315. doi: 10.1038/ng.300

PubMed Abstract | CrossRef Full Text | Google Scholar

Glinka, Y., Gassen, M., and Youdim, M. B. H. (1997). Mechanism of 6-hydroxydopamine neurotoxicity. J. Neural Transm. 50(Suppl.), 55–66. doi: 10.1007/978-3-7091-6842-4_7

PubMed Abstract | CrossRef Full Text | Google Scholar

Glinka, Y., Tipton, K. F., and Youdim, M. B. (1998). Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine. Eur. J. Pharmacol. 351, 121–129. doi: 10.1016/S0014-2999(98)00279-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., O'neill, E., Meitinger, T., et al. (2006). The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum. Mol. Genet. 15, 223–232. doi: 10.1093/hmg/ddi439

PubMed Abstract | CrossRef Full Text | Google Scholar

Goldman, S. M., Quinlan, P. J., Ross, G. W., Marras, C., Meng, C., Bhudhikanok, G. S., et al. (2012). Solvent exposures and Parkinson disease risk in twins. Ann. Neurol. 71, 776–784. doi: 10.1002/ana.22629

PubMed Abstract | CrossRef Full Text | Google Scholar

Gonzalez-Hunt, C. P., Leung, M. C., Bodhicharla, R. K., Mckeever, M. G., Arrant, A. E., Margillo, K. M., et al. (2014). Exposure to mitochondrial genotoxins and dopaminergic neurodegeneration in Caenorhabditis elegans. PLoS ONE 9:114459. doi: 10.1371/journal.pone.0114459

PubMed Abstract | CrossRef Full Text | Google Scholar

Gordon, P., Hingula, L., Krasny, M. L., Swienckowski, J. L., Pokrywka, N. J., and Raley-Susman, K. M. (2008). The invertebrate microtubule-associated protein PTL-1 functions in mechanosensation and development in Caenorhabditis elegans. Dev. Genes Evol. 218, 541–551. doi: 10.1007/s00427-008-0250-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Gray, J. M., Hill, J. J., and Bargmann, C. I. (2005). A circuit for navigation in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 102, 3184–3191. doi: 10.1073/pnas.0409009101

PubMed Abstract | CrossRef Full Text | Google Scholar

Greengard, P. (2001). The neurobiology of dopamine signaling. Biosci. Rep. 21, 247–269. doi: 10.1023/A:1013205230142

PubMed Abstract | CrossRef Full Text | Google Scholar

Grover, S., Somaiya, M., Kumar, S., and Avasthi, A. (2015). Psychiatric aspects of Parkinson's disease. J. Neurosci. Rural Pract. 6, 65–76. doi: 10.4103/0976-3147.143197

PubMed Abstract | CrossRef Full Text | Google Scholar

Groves, P. M. (1983). A theory of the functional organization of the neostriatum and the neostriatal control of voluntary movement. Brain Res. 286, 109–132. doi: 10.1016/0165-0173(83)90011-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Guo, M. (2012). Drosophila as a model to study mitochondrial dysfunction in Parkinson's disease. Cold Spring Harb. Perspect. Med. 2, 1–18. doi: 10.1101/cshperspect.a009944

PubMed Abstract | CrossRef Full Text

Hamamichi, S., Rivas, R. N., Knight, A. L., Cao, S., Caldwell, K. A., and Caldwell, G. A. (2008). Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model. Proc. Natl. Acad. Sci. U.S.A. 105, 728–733. doi: 10.1073/pnas.0711018105

PubMed Abstract | CrossRef Full Text | Google Scholar

Harrington, A. J., Hamamichi, S., Caldwell, G. A., and Caldwell, K. A. (2010). C. elegans as a model organism to investigate molecular pathways involved with Parkinson's Disease. Develop. Dyn. 239, 1282–1295. doi: 10.1002/dvdy.22231

PubMed Abstract | CrossRef Full Text | Google Scholar

Hatano, T., Kubo, S., Imai, S., Maeda, M., Ishikawa, K., Mizuno, Y., et al. (2007). Leucine-rich repeat kinase 2 associates with lipid rafts. Hum. Mol. Genet. 16, 678–690. doi: 10.1093/hmg/ddm013

PubMed Abstract | CrossRef Full Text | Google Scholar

Hausdorff, J. M., Cudkowicz, M. E., Firtion, R., Wei, J. Y., and Goldberger, A. L. (1998). Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson's disease and Huntington's disease. Mov. Disord. 13, 428–437. doi: 10.1002/mds.870130310

PubMed Abstract | CrossRef Full Text | Google Scholar

Healy, D. G., Falchi, M., O'sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., et al. (2008). Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 7, 583–590. doi: 10.1016/S1474-4422(08)70117-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Heiner, F., Feistel, B., and Wink, M. (2015). Sideritis scardica extracts inhibit the aggregation of alpha-synuclein and beta-amyloid peptides in Caenorhabditis elegans used as a model for neurodegenerative diseases. Planta Med. 81, 1527–1527. doi: 10.1055/s-0035-1565751

CrossRef Full Text | Google Scholar

Herndon, L. A., Schmeissner, P. J., Dudaronek, J. M., Brown, P. A., Listner, K. M., Sakano, Y., et al. (2002). Stochastic and genetic factors influence tissue-specific decline in ageing C-elegans. Nature 419, 808–814. doi: 10.1038/nature01135

PubMed Abstract | CrossRef Full Text | Google Scholar

Hills, T., Brockie, P. J., and Maricq, A. V. (2004). Dopamine and glutamate control area-restricted search behavior in Caenorhabditis elegans. J. Neurosci. 24, 1217–1225. doi: 10.1523/JNEUROSCI.1569-03.2004

PubMed Abstract | CrossRef Full Text | Google Scholar

Ho, C. C., Rideout, H. J., Ribe, E., Troy, C. M., and Dauer, W. T. (2009). The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J. Neurosci. 29, 1011–1016. doi: 10.1523/JNEUROSCI.5175-08.2009

PubMed Abstract | CrossRef Full Text | Google Scholar

Hodgkin, J., and Barnes, T. M. (1991). More is not better: brood size and population growth in a self-fertilizing nematode. Proc. Biol. Sci. 246, 19–24. doi: 10.1098/rspb.1991.0119

PubMed Abstract | CrossRef Full Text | Google Scholar

Horning, K. J., Caito, S. W., Tipps, K. G., Bowman, A. B., and Aschner, M. (2015). Manganese is essential for neuronal health. Annu. Rev. Nutr. 35, 71–108. doi: 10.1146/annurev-nutr-071714-034419

PubMed Abstract | CrossRef Full Text | Google Scholar

Husson, S. J., Costa, W. S., Schmitt, C., and Gottschalk, A. (2013). Keeping track of worm trackers. WormBook 1–17. doi: 10.1895/wormbook.1.156.1

PubMed Abstract | CrossRef Full Text | Google Scholar

Hwang, O. (2013). Role of oxidative stress in Parkinson's disease. Exp. Neurobiol. 22, 11–17. doi: 10.5607/en.2013.22.1.11

PubMed Abstract | CrossRef Full Text | Google Scholar

Imai, Y., Gehrke, S., Wang, H. Q., Takahashi, R., Hasegawa, K., Oota, E., et al. (2008). Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. EMBO J. 27, 2432–2443. doi: 10.1038/emboj.2008.163

PubMed Abstract | CrossRef Full Text | Google Scholar

Jadiya, P., Khan, A., Sammi, S. R., Kaur, S., Mir, S. S., and Nazir, A. (2011). Anti-Parkinsonian effects of Bacopa monnieri: insights from transgenic and pharmacological Caenorhabditis elegans models of Parkinson's disease. Biochem. Biophys. Res. Commun. 413, 605–610. doi: 10.1016/j.bbrc.2011.09.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Jadiya, P., Mir, S. S., and Nazir, A. (2012). Effect of various classes of pesticides on expression of stress genes in transgenic C. elegans model of Parkinson's disease. CNS Neurol. Disord. Drug Targets 11, 1001–1005. doi: 10.2174/1871527311211080009

PubMed Abstract | CrossRef Full Text | Google Scholar

Jadiya, P., and Nazir, A. (2012). Environmental Toxicants as Extrinsic Epigenetic Factors for Parkinsonism: studies employing transgenic C. elegans Model. CNS Neurol. Disord. Drug Targets 11, 976–983. doi: 10.2174/1871527311211080006

PubMed Abstract | CrossRef Full Text | Google Scholar

Jagmag, S. A., Tripathi, N., Shukla, S. D., Maiti, S., and Khurana, S. (2015). Evaluation of models of Parkinson's disease. Front. Neurosci. 9:503. doi: 10.3389/fnins.2015.00503

PubMed Abstract | CrossRef Full Text | Google Scholar

Jankovic, J. (2008). Parkinson's disease: clinical features and diagnosis. J. Neurol. Neurosurg. Psychiatr. 79, 368–376. doi: 10.1136/jnnp.2007.131045

PubMed Abstract | CrossRef Full Text | Google Scholar

Jensen, L. T., Moller, T. H., Larsen, S. A., Jakobsen, H., and Olsen, A. (2012). A new role for laminins as modulators of protein toxicity in Caenorhabditis elegans. Aging Cell 11, 82–92. doi: 10.1111/j.1474-9726.2011.00767.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, G. C., Tidwell, K., Mclaughlin, B. A., Cai, J., Gupta, R. C., Milatovic, D., et al. (2007). Neurotoxic potential of depleted uranium effects in primary cortical neuron cultures and in Caenorhabditis elegans. Toxicol. Sci. 99, 553–565. doi: 10.1093/toxsci/kfm171

PubMed Abstract | CrossRef Full Text | Google Scholar

Johnson, W. M., Yao, C., Siedlak, S. L., Wang, W., Zhu, X., Caldwell, G. A., et al. (2015). Glutaredoxin deficiency exacerbates neurodegeneration in C. elegans models of Parkinson's disease. Hum. Mol. Genet. 24, 1322–1335. doi: 10.1093/hmg/ddu542

PubMed Abstract | CrossRef Full Text | Google Scholar

Jorgensen, E. M., and Mango, S. E. (2002). The art and design of genetic screens: Caenorhabditis Elegans. Nat. Rev. Genet. 3, 356–369. doi: 10.1038/nrg794

PubMed Abstract | CrossRef Full Text | Google Scholar

Jung, J., Nakajima, M., Takeuchi, M., Najdovski, Z., Huang, Q., and Fukuda, T. (2016). Microfluidic device to measure the speed of C. elegans using the resistance change of the flexible electrode. Micromachines 7:50. doi: 10.3390/mi7030050

CrossRef Full Text | Google Scholar

Kalia, L. V., and Lang, A. E. (2015). Parkinson's disease. Lancet 386, 896–912. doi: 10.1016/S0140-6736(14)61393-3

PubMed Abstract | CrossRef Full Text

Kanao, T., Venderova, K., Park, D. S., Unterman, T., Lu, B., and Imai, Y. (2010). Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila. Hum. Mol. Genet. 19, 3747–3758. doi: 10.1093/hmg/ddq289

PubMed Abstract | CrossRef Full Text | Google Scholar

Karpinar, D. P., Balija, M. B., Kugler, S., Opazo, F., Rezaei-Ghaleh, N., Wender, N., et al. (2009). Pre-fibrillar alpha-synuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. EMBO J. 28, 3256–3268. doi: 10.1038/emboj.2009.257

PubMed Abstract | CrossRef Full Text | Google Scholar

Kautu, B. B., Carrasquilla, A., Hicks, M. L., Caldwell, K. A., and Caldwell, G. A. (2013). Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling. Neurosci. Lett. 541, 116–119. doi: 10.1016/j.neulet.2013.02.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Kenyon, C., Chang, J., Gensch, E., Rudner, A., and Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464. doi: 10.1038/366461a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Kimura, K. D., Fujita, K., and Katsura, I. (2010). Enhancement of odor avoidance regulated by dopamine signaling in Caenorhabditis elegans. J. Neurosci. 30, 16365–16375. doi: 10.1523/JNEUROSCI.6023-09.2010

PubMed Abstract | CrossRef Full Text | Google Scholar

Klein, C., and Westenberger, A. (2012). Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2:a008888. doi: 10.1101/cshperspect.a008888

PubMed Abstract | CrossRef Full Text | Google Scholar

Koepp, M. J., Gunn, R. N., Lawrence, A. D., Cunningham, V. J., Dagher, A., Jones, T., et al. (1998). Evidence for striatal dopamine release during a video game. Nature 393, 266–268. doi: 10.1038/30498

PubMed Abstract | CrossRef Full Text | Google Scholar

Kuwahara, T., Koyama, A., Gengyo-Ando, K., Masuda, M., Kowa, H., Tsunoda, M., et al. (2006). Familial Parkinson mutant α-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J. Biol. Chem. 281, 334–340. doi: 10.1074/jbc.M504860200

PubMed Abstract | CrossRef Full Text | Google Scholar

Kuwahara, T., Koyama, A., Koyama, S., Yoshina, S., Ren, C. H., Kato, T., et al. (2008). A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in α-synuclein transgenic C. elegans. Hum. Mol. Genet. 17, 2997–3009. doi: 10.1093/hmg/ddn198

PubMed Abstract | CrossRef Full Text | Google Scholar

Kwan, C. S., Vázquez-Manrique, R. P., Ly, S., Goyal, K., and Baylis, H. A. (2008). TRPM channels are required for rhythmicity in the ultradian defecation rhythm of C. elegans. BMC Physiol. 8:11. doi: 10.1186/1472-6793-8-11

PubMed Abstract | CrossRef Full Text | Google Scholar

Lai, C. H., Chou, C. Y., Ch'ang, L. Y., Liu, C. S., and Lin, W. (2000). Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 10, 703–713. doi: 10.1101/gr.10.5.703

PubMed Abstract | CrossRef Full Text | Google Scholar

Lakso, M., Vartiainen, S., Moilanen, A.-M., Sirviö, J., Thomas, J. H., Nass, R., et al. (2003). Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α-synuclein. J. Neurochem. 86, 165–172. doi: 10.1046/j.1471-4159.2003.01809.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Lanciego, J. L., Luquin, N., and Obeso, J. A. (2012). Functional neuroanatomy of the basal ganglia. Cold Spring Harb. Perspect. Med. 2:a009621. doi: 10.1101/cshperspect.a009621

PubMed Abstract | CrossRef Full Text | Google Scholar

Langston, J. W., Ballard, P., Tetrud, J. W., and Irwin, I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219, 979–980. doi: 10.1126/science.6823561

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, D., Lee, S.-Y., Lee, E.-N., Chang, C.-S., and Paik, S. R. (2002). α-Synuclein exhibits competitive interaction between calmodulin and synthetic membranes. J. Neurochem. 82, 1007–1017. doi: 10.1046/j.1471-4159.2002.01024.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J., Jee, C., and Mcintire, S. L. (2009). Ethanol preference in C elegans. Genes Brain Behav. 8, 578–585. doi: 10.1111/j.1601-183X.2009.00513.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J. Y., Song, J., Kwon, K., Jang, S., Kim, C., Baek, K., et al. (2012). Human DJ-1 and its homologs are novel glyoxalases. Hum. Mol. Genet. 21, 3215–3225. doi: 10.1093/hmg/dds155

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J. W., and Cannon, J. R. (2015). LRRK2 mutations and neurotoxicant susceptibility. Exp. Biol. Med. 240, 752–759. doi: 10.1177/1535370215579162

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, J., Zhu, W. M., Stanic, D., Finkelstein, D. I., Horne, M. H., Henderson, J., et al. (2008). Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia. Brain 131, 1574–1587. doi: 10.1093/brain/awn085

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, R. C., and Ambros, V. (2001). An extensive class of small RNAs in Caenorhabditis elegans Science 294, 862–864. doi: 10.1126/science.1065329

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, R. Y., Hench, J., and Ruvkun, G. (2001). Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr. Biol. 11, 1950–1957. doi: 10.1016/S0960-9822(01)00595-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Leung, M. C. K., Williams, P. L., Benedetto, A., Au, C., Helmcke, K. J., Aschner, M., et al. (2008). Caenorhabditis elegans: an emerging model in biomedical and environmental toxicology. Toxicol. Sci. 106, 5–28. doi: 10.1093/toxsci/kfn121

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, H., Shi, R., Ding, F., Wang, H., Han, W., Ma, F., et al. (2016). Astragalus Polysaccharide Suppresses 6-Hydroxydopamine-Induced Neurotoxicity in Caenorhabditis elegans. Oxid. Med. Cell. Longev. 2016:4856761. doi: 10.1155/2016/4856761

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, J., Li, D., Yang, Y. S., Xu, T. T., Li, P., and He, D. F. (2016). Acrylamide induces locomotor defects and degeneration of dopamine neurons in Caenorhabditis elegans. J. Appl. Toxicol. 36, 60–67. doi: 10.1002/jat.3144

PubMed Abstract | CrossRef Full Text | Google Scholar

Liou, H. H., Tsai, M. C., Chen, C. J., Jeng, J. S., Chang, Y. C., Chen, S. Y., et al. (1997). Environmental risk factors and Parkinson's disease: a case-control study in Taiwan. Neurology 48, 1583–1588. doi: 10.1212/WNL.48.6.1583

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, J., Banskota, A. H., Critchley, A. T., Hafting, J., and Prithiviraj, B. (2015). Neuroprotective effects of the cultivated Chondrus crispus in a C. elegans Model of Parkinson's Disease. Marine Drugs 13, 2250–2266. doi: 10.3390/md13042250

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, K. S., and Sternberg, P. W. (1995). Sensory regulation of male mating behavior in caenorhabditis elegans. Neuron 14, 79–89. doi: 10.1016/0896-6273(95)90242-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Loer, C. M., and Kenyon, C. J. (1993). Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans. J. Neurosci. 13, 5407–5417.

PubMed Abstract | Google Scholar

Longo, F., Mercatelli, D., Novello, S., Arcuri, L., Brugnoli, A., Vincenzi, F., et al. (2017). Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice. Acta Neuropathol. Commun, 5:22. doi: 10.1186/s40478-017-0426-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Lücking, C. B., Dürr, A., Bonifati, V., Vaughan, J., De Michele, G., Gasser, T., et al. (2000). Association between early-onset Parkinson's disease and mutations in the parkin gene. N. Engl. J. Med. 342, 1560–1567. doi: 10.1056/NEJM200005253422103

PubMed Abstract | CrossRef Full Text | Google Scholar

Manning-Bog, A. B., Mccormack, A. L., Li, J., Uversky, V. N., Fink, A. L., and Di Monte, D. A. (2002). The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J. Biol. Chem. 277, 1641–1644. doi: 10.1074/jbc.C100560200

PubMed Abstract | CrossRef Full Text | Google Scholar

Marsden, C. D. (1982). The Mysterious Motor Function of the Basal Ganglia - the Robert Wartenberg Lecture. Neurology 32, 514–539. doi: 10.1212/WNL.32.5.514

PubMed Abstract | CrossRef Full Text | Google Scholar

Martinez-Finley, E. J., Chakraborty, S., Slaughter, J. C., and Aschner, M. (2013). Early-life exposure to methylmercury in wildtype and pdr-1/parkin knockout C. elegans. Neurochem. Res. 38, 1543–1552. doi: 10.1007/s11064-013-1054-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Marvanova, M., and Nichols, C. D. (2007). Identification of neuroprotective compounds of Caenorhabditis elegans dopaminergic neurons against 6-OHDA. J. Mol. Neurosci. 31, 127–137. doi: 10.1385/JMN/31:02:127

PubMed Abstract | CrossRef Full Text | Google Scholar

Masoudi, N., Ibanez-Cruceyra, P., Offenburger, S. L., Holmes, A., and Gartner, A. (2014). Tetraspanin (TSP-17) Protects Dopaminergic Neurons against 6-OHDA-Induced Neurodegeneration in C. elegans. PLoS Genet. 10:e1004767. doi: 10.1371/journal.pgen.1004767

PubMed Abstract | CrossRef Full Text | Google Scholar

McDonald, P. W., Hardie, S. L., Jessen, T. N., Carvelli, L., Matthies, D. S., and Blakely, R. D. (2007). Vigorous motor activity in Caenorhabditis elegans requires efficient clearance of dopamine mediated by synaptic localization of the dopamine transporter DAT-1. J. Neurosci. 27, 14216–14227. doi: 10.1523/JNEUROSCI.2992-07.2007

PubMed Abstract | CrossRef Full Text | Google Scholar

McDonald, P. W., Jessen, T., Field, J. R., and Blakely, R. D. (2006). Dopamine signaling architecture in Caenorhabditis elegans. Cell. Mol. Neurobiol. 26, 593–618. doi: 10.1007/s10571-006-9003-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Melentijevic, I., Toth, M. L., Arnold, M. L., Guasp, R. J., Harinath, G., Nguyen, K. C., et al. (2017). C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. Nature 542, 367–371. doi: 10.1038/nature21362

PubMed Abstract | CrossRef Full Text | Google Scholar

Meredith, G. E., and Rademacher, D. J. (2011). MPTP mouse models of Parkinson's disease: an update. J. Parkinsons Dis. 1, 19–33. doi: 10.3233/JPD-2011-11023

PubMed Abstract | CrossRef Full Text | Google Scholar

Meredith, G. E., Totterdell, S., Potashkin, J. A., and Surmeier, D. J. (2008). Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat. Disord. 14(Suppl. 2), S112–S115 doi: 10.1016/j.parkreldis.2008.04.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Mesce, K. A., and Pierce-Shimomura, J. T. (2010). Shared strategies for behavioral switching: understanding how locomotor patterns are turned on and off. Front. Behav. Neurosci. 4:49. doi: 10.3389/fnbeh.2010.00049

PubMed Abstract | CrossRef Full Text | Google Scholar

Michel, P. P., Toulorge, D., Guerreiro, S., and Hirsch, E. C. (2013). Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease. FASEB J. 27, 3414–3423. doi: 10.1096/fj.12-220418

PubMed Abstract | CrossRef Full Text | Google Scholar

Miller, R. L., Sun, G. Y., and Sun, A. Y. (2007). Cytotoxicity of paraquat in microglial cells: involvement of the PKC- and ERK 1/2-dependent NADPH oxidase. J. Neurochem. 102, 55–56. doi: 10.1016/j.brainres.2007.06.046

CrossRef Full Text

Mink, J. W., and Thach, W. T. (1991). Basal Ganglia Motor Control 0.1. Nonexclusive Relation of Pallidal Discharge to 5 Movement Modes. J. Neurophysiol. 65, 273–300.

PubMed Abstract | Google Scholar

Miyara, M., Kotake, Y., Tokunaga, W., Sanoh, S., and Ohta, S. (2016). Mild MPP+ exposure impairs autophagic degradation through a novel lysosomal acidity-independent mechanism. J. Neurochem. 139, 294–308. doi: 10.1111/jnc.13700

PubMed Abstract | CrossRef Full Text | Google Scholar

Miyasaka, T., Ding, Z., Gengyo-Ando, K., Oue, M., Yamaguchi, H., Mitani, S., et al. (2005). Progressive neurodegeneration in C. elegans model of tauopathy. Neurobiol. Dis. 20, 372–383. doi: 10.1016/j.nbd.2005.03.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Morimoto, R. I. (2008). Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438. doi: 10.1101/gad.1657108

PubMed Abstract | CrossRef Full Text | Google Scholar

Morimoto, R. I., Kline, M. P., Bimston, D. N., and Cotto, J. J. (1997). The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem. 32, 17–29.

PubMed Abstract

Morris, M. E., Iansek, R., Matyas, T. A., and Summers, J. J. (1996). Stride length regulation in Parkinson's disease. Normalization strategies and underlying mechanisms. Brain 119(Pt 2), 551–568. doi: 10.1093/brain/119.2.551

PubMed Abstract | CrossRef Full Text | Google Scholar

Munoz-Lobato, F., Rodriguez-Palero, M. J., Naranjo-Galindo, F. J., Shephard, F., Gaffney, C. J., Szewczyk, N. J., et al. (2014). Protective Role of DNJ-27/ERdj5 in Caenorhabditis elegans Models of Human Neurodegenerative Diseases. Antioxid. Redox Signal. 20, 217–235. doi: 10.1089/ars.2012.5051

PubMed Abstract | CrossRef Full Text | Google Scholar

Myers, J. E., Tewaternaude, J., Fourie, M., Zogoe, H. B., Naik, I., Theodorou, P., et al. (2003). Nervous system effects of occupational manganese exposure on South African manganese mineworkers. Neurotoxicology 24, 649–656. doi: 10.1016/S0161-813X(03)00035-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Nagakubo, D., Taira, T., Kitaura, H., Ikeda, M., Tamai, K., Iguchi-Ariga, S. M., et al. (1997). DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation withras. Biochem. Biophys. Res. Commun. 231, 509–513. doi: 10.1006/bbrc.1997.6132

PubMed Abstract | CrossRef Full Text | Google Scholar

Nass, R., and Blakely, R. D. (2003). The Caenorhabditis elegans dopaminergic system: opportunities for insights into dopamine transport and neurodegeneration. Annu. Rev. Pharmacol. Toxicol. 43, 521–544. doi: 10.1146/annurev.pharmtox.43.100901.135934

PubMed Abstract | CrossRef Full Text | Google Scholar

Nass, R., Hahn, M. K., Jessen, T., Mcdonald, P. W., Carvelli, L., and Blakely, R. D. (2005). A genetic screen in Caenorhabditis elegans for dopamine neuron insensitivity to 6-hydroxydopamine identifies dopamine transporter mutants impacting transporter biosynthesis and trafficking. J. Neurochem. 94, 774–785. doi: 10.1111/j.1471-4159.2005.03205.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Nass, R., Hall, D. H., Miller, D. M., and Blakely, R. D. (2002). Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 99, 3264–3269. doi: 10.1073/pnas.042497999

PubMed Abstract | CrossRef Full Text | Google Scholar

Nass, R., Miller, D. M., and Blakely, R. D. (2001). C. elegans: a novel pharmacogenetic model to study Parkinson's disease. Parkinsonism Relat. Disord. 7, 185–191. doi: 10.1016/S1353-8020(00)00056-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Nemani, V. M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M. K., et al. (2010). Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79. doi: 10.1016/j.neuron.2009.12.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Nidheesh, T., Salim, C., Rajini, P. S., and Suresh, P. V. (2016). Antioxidant and neuroprotective potential of chitooligomers in Caenorhabditis elegans exposed to Monocrotophos. Carbohydr. Polym. 135, 138–144. doi: 10.1016/j.carbpol.2015.08.055

PubMed Abstract | CrossRef Full Text | Google Scholar

Olanow, C. W. (2004). Manganese-induced parkinsonism and parkinson's disease. Anna. N.Y. Acad. Sci. 1012, 209–223. doi: 10.1196/annals.1306.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Omura, D. T., Clark, D. A., Samuel, A. D. T., and Horvitz, H. R. (2012). Dopamine signaling is essential for precise rates of locomotion by C. elegans. PLOS ONE 7:e38649. doi: 10.1371/journal.pone.0038649

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Reilly, L. P., Luke, C. J., Perlmutter, D. H., Silverman, G. A., and Pak, S. C. (2014). C. elegans in high-throughput drug discovery Adv. Drug Deliv. Rev. 69–70, 247–253. doi: 10.1016/j.addr.2013.12.001

PubMed Abstract | CrossRef Full Text

O'Rourke, E. J., Soukas, A. A., Carr, C. E., and Ruvkun, G. (2009). C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metab 10, 430–435. doi: 10.1016/j.cmet.2009.10.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Paisán-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simo, J., Munain, D., et al. (2004). Cloning of the gene containing mutations that cause PARK8 -Linked Parkinson's disease. Neuron 44, 595–600. doi: 10.1016/j.neuron.2004.10.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Parker, J. A., Connolly, J. B., Wellington, C., Hayden, M., Dausset, J., and Neri, C. (2001). Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc. Natl. Acad. Sci. U.S.A. 98, 13318–13323. doi: 10.1073/pnas.231476398

PubMed Abstract | CrossRef Full Text | Google Scholar

Pehek, E. A., Nocjar, C., Roth, B. L., Byrd, T. A., and Mabrouk, O. S. (2005). Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31, 265–277. doi: 10.1038/sj.npp.1300819

PubMed Abstract | CrossRef Full Text | Google Scholar

Pickel, V. M., Beckley, S. C., Joh, T. H., and Reis, D. J. (1981). Ultrastructural immunocytochemical localization of tyrosine hydroxylase in the neostriatum. Brain Res. 225, 373–385. doi: 10.1016/0006-8993(81)90843-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Pierce-Shimomura, J. T., Chen, B. L., Mun, J. J., Ho, R., Sarkis, R., and Mcintire, S. L. (2008). Genetic analysis of crawling and swimming locomotory patterns in C. elegans. Proc. Natl. Acad. Sci. U.S.A. 105, 20982–20987. doi: 10.1073/pnas.0810359105

PubMed Abstract | CrossRef Full Text | Google Scholar

Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., et al. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047. doi: 10.1126/science.276.5321.2045

PubMed Abstract | CrossRef Full Text | Google Scholar

Prohaska, J. R. (1987). Functions of trace elements in brain metabolism. Physiol. Rev. 67, 858–901.

PubMed Abstract | Google Scholar

Pu, P., and Le, W. (2008). Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans. Cell Res. 18, 978–981. doi: 10.1038/cr.2008.279

PubMed Abstract | CrossRef Full Text | Google Scholar

Ray, A., Martinez, B. A., Berkowitz, L. A., Caldwell, G. A., and Caldwell, K. A. (2014). Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model. Cell Death Dis. 5:e983. doi: 10.1038/cddis.2013.513

PubMed Abstract | CrossRef Full Text | Google Scholar

Ribeiro, F. M., Camargos, E. R., De Souza, L. C., and Teixeira, A. L. (2013). Animal models of neurodegenerative diseases. Rev. Bras. Psiquiatr. 35(Suppl. 2), S82–S91. doi: 10.1590/1516-4446-2013-1157

PubMed Abstract | CrossRef Full Text | Google Scholar

Rivard, L., Srinivasan, J., Stone, A., Ochoa, S., Sternberg, P. W., and Loer, C. M. (2010). A comparison of experience-dependent locomotory behaviors and biogenic amine neurons in nematode relatives of Caenorhabditis elegans. BMC Neurosci. 11:22. doi: 10.1186/1471-2202-11-22

PubMed Abstract | CrossRef Full Text | Google Scholar

Rose, J. K., and Rankin, C. H. (2001). Analyses of habituation in Caenorhabditis elegans. Learn. Mem. 8, 63–69. doi: 10.1101/lm.37801

PubMed Abstract | CrossRef Full Text | Google Scholar

Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A., et al. (2008). Genomic investigation of α-synuclein multiplication and parkinsonism. Ann. Neurol. 63, 743–750. doi: 10.1002/ana.21380

PubMed Abstract | CrossRef Full Text | Google Scholar

Russell, J. A., Ciucci, M. R., Connor, N. P., and Schallert, T. (2010). Targeted exercise therapy for voice and swallow in persons with Parkinson's disease. Brain Res. 1341, 3–11. doi: 10.1016/j.brainres.2010.03.029

PubMed Abstract | CrossRef Full Text | Google Scholar

Sakaguchi-Nakashima, A., Meir, J. Y., Jin, Y., Matsumoto, K., and Hisamoto, N. (2007). LRK-1, a C. elegans PARK8-Related Kinase, Regulates Axonal-Dendritic Polarity of SV Proteins. Curr. Biol. 17, 592–598. doi: 10.1016/j.cub.2007.01.074

PubMed Abstract | CrossRef Full Text | Google Scholar

Sämann, J., Hegermann, J., Von Gromoff, E., Eimer, S., Baumeister, R., and Schmidt, E. (2009). Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. J. Biol. Chem. 284, 16482–16491. doi: 10.1074/jbc.M808255200

PubMed Abstract | CrossRef Full Text | Google Scholar

Samii, A., Nutt, J. G., and Ransom, B. R. (2004). Parkinson's disease Lancet. 363, 1783–1793 doi: 10.1016/s0140-6736(04)16305-8

PubMed Abstract | CrossRef Full Text

Sanders, J., Nagy, S., Fetterman, G., Wright, C., Treinin, M., and Biron, D. (2013). The Caenorhabditis elegans interneuron ALA is (also) a high-threshold mechanosensor. BMC Neurosci. 14:156. doi: 10.1186/1471-2202-14-156

PubMed Abstract | CrossRef Full Text | Google Scholar

Sanyal, S., Wintle, R. F., Kindt, K. S., Nuttley, W. M., Arvan, R., Fitzmaurice, P., et al. (2004). Dopamine modulates the plasticity of mechanosensory responses in Caenorhabditis elegans. Embo J. 23, 473–482. doi: 10.1038/sj.emboj.7600057

PubMed Abstract | CrossRef Full Text | Google Scholar

Sashidhara, K. V., Modukuri, R. K., Jadiya, P., Rao, K. B., Sharma, T., Haque, R., et al. (2014). Discovery of 3-Arylcoumarin-tetracyclic Tacrine Hybrids as multifunctional agents against Parkinson's disease. ACS Med. Chem. Lett. 5, 1099–1103. doi: 10.1021/ml500222g

PubMed Abstract | CrossRef Full Text | Google Scholar

Satapathy, P., Salim, C., Naidu, M. M., and Ps, R. (2016). Attenuation of dopaminergic neuronal dysfunction in Caenorhabditis elegans by Hydrophilic Form of Curcumin. Neurochem. Neuropharmacol. 2:111. doi: 10.4172/2469-9780.1000111

CrossRef Full Text

Satyal, S. H., Schmidt, E., Kitagawa, K., Sondheimer, N., Lindquist, S., Kramer, J. M., et al. (2000). Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 97, 5750–5755. doi: 10.1073/pnas.100107297

PubMed Abstract | CrossRef Full Text | Google Scholar

Sawin, E. R., Ranganathan, R., and Horvitz, H. R. (2000). C-elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26, 619–631. doi: 10.1016/S0896-6273(00)81199-X

PubMed Abstract | CrossRef Full Text | Google Scholar

Scerbak, C., Vayndorf, E. M., Hernandez, A., Mcgill, C., and Taylor, B. E. (2016). Mechanosensory neuron aging: differential trajectories with lifespan-extending alaskan berry and fungal treatments in Caenorhabditis elegans. Front. Aging Neurosci. 8:173. doi: 10.3389/fnagi.2016.00173

PubMed Abstract | CrossRef Full Text | Google Scholar

Scerbak, C., Vayndorf, E. M., Parker, J. A., Neri, C., Driscoll, M., and Taylor, B. E. (2014). Insulin signaling in the aging of healthy and proteotoxically stressed mechanosensory neurons. Front. Genet. 5:212. doi: 10.3389/fgene.2014.00212

PubMed Abstract | CrossRef Full Text | Google Scholar

Schafer, W. R., and Kenyon, C. J. (1995). A Calcium-Channel Homolog Required for Adaptation to Dopamine and Serotonin in Caenorhabditis-Elegans. Nature 375, 73–78. doi: 10.1038/375073a0

PubMed Abstract | CrossRef Full Text | Google Scholar

Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., et al. (2012). Fiji: an open-source platform for biological-image analysis. Nat. Meth. 9, 676–682. doi: 10.1038/nmeth.2019

PubMed Abstract | CrossRef Full Text | Google Scholar

Schirinzi, T., Madeo, G., Martella, G., Maltese, M., Picconi, B., Calabresi, P., et al. (2016). Early synaptic dysfunction in Parkinson's disease: insights from animal models. Mov. Disord. 31, 802–813. doi: 10.1002/mds.26620

PubMed Abstract | CrossRef Full Text | Google Scholar

Schultz, W. (2007). Multiple dopamine functions at different time courses. Annu. Rev. Neurosci. 30, 259–288. doi: 10.1146/annurev.neuro.28.061604.135722

PubMed Abstract | CrossRef Full Text | Google Scholar

Senoh, S., Creveling, C. R., Udenfriend, S., and Witkop, B. (1959). Chemical, Enzymatic and Metabolic Studies on the Mechanism of Oxidation of Dopamine1. J. Am. Chem. Soc. 81, 6236–6240. doi: 10.1021/ja01532a030

CrossRef Full Text | Google Scholar

Senoh, S., and Witkop, B. (1959). Non-enzymatic Conversions of Dopamine to Norepinephrine and Trihydroxyphenethylamines1. J. Am. Chem. Soc. 81, 6222–6231. doi: 10.1021/ja01532a028

CrossRef Full Text | Google Scholar

Settivari, R., Levora, J., and Nass, R. (2009). The divalent metal transporter homologues SMF-1/2 mediate dopamine neuron sensitivity in Caenorhabditis elegans models of manganism and parkinson disease. J. Biol. Chem. 284, 35758–35768. doi: 10.1074/jbc.M109.051409

PubMed Abstract | CrossRef Full Text | Google Scholar

Settivari, R., Vanduyn, N., Levora, J., and Nass, R. (2013). The Nrf2/SKN-1-dependent glutathione S-transferase pi homologue GST-1 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of manganism. Neurotoxicology 38, 51–60. doi: 10.1016/j.neuro.2013.05.014

PubMed Abstract | CrossRef Full Text | Google Scholar

Shaye, D. D., and Greenwald, I. (2011). Ortholist: A compendium of C. elegans genes with human orthologs. PLoS ONE 6:20085. doi: 10.1371/journal.pone.0020085

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, Z., Lu, Z., Zhao, Y., Wang, Y., Zhao-Wilson, X., Guan, P., et al. (2013). Neuroprotective effects of aqueous extracts of Uncaria tomentosa: insights from 6-OHDA induced cell damage and transgenic Caenorhabditis elegans model. Neurochem. Int. 62, 940–947. doi: 10.1016/j.neuint.2013.03.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Shin, N., Jeong, H., Kwon, J., Heo, H. Y., Kwon, J. J., Yun, H. J., et al. (2008). LRRK2 regulates synaptic vesicle endocytosis. Exp. Cell Res. 314, 2055–2065. doi: 10.1016/j.yexcr.2008.02.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Shukla, V., Phulara, S. C., Yadav, D., Tiwari, S., Kaur, S., Gupta, M. M., et al. (2012). Iridoid compound 10-O-trans-p-coumaroylcatalpol extends longevity and reduces alpha synuclein aggregation in Caenorhabditis elegans. CNS Neurol. Disord. Drug Targets 11, 984–992. doi: 10.2174/1871527311211080007

PubMed Abstract | CrossRef Full Text | Google Scholar

Singleton, A. B., Farrer, M. J., and Bonifati, V. (2013). The genetics of Parkinson's disease: progress and therapeutic implications. Mov. Disord. 28, 14–23. doi: 10.1002/mds.25249

PubMed Abstract | CrossRef Full Text | Google Scholar

Smeyne, M., Jiao, Y., Shepherd, K. R., and Smeyne, R. J. (2005). Glia cell number modulates sensitivity to MPTP in mice. Glia 52, 144–152. doi: 10.1002/glia.20233

PubMed Abstract | CrossRef Full Text | Google Scholar

Smith, W. W., Pei, Z., Jiang, H., Moore, D. J., Liang, Y., West, A. B., et al. (2005). Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc. Natl. Acad. Sci. U.S.A. 102, 18676–18681. doi: 10.1073/pnas.0508052102

PubMed Abstract | CrossRef Full Text | Google Scholar

Snead, D., and Eliezer, D. (2014). Alpha-synuclein function and dysfunction on cellular membranes. Exp. Neurobiol. 23, 292–313. doi: 10.5607/en.2014.23.4.292

PubMed Abstract | CrossRef Full Text | Google Scholar

Sofuwa, O., Nieuwboer, A., Desloovere, K., Willems, A. M., Chavret, F., and Jonkers, I. (2005). Quantitative gait analysis in Parkinson's disease: comparison with a healthy control group. Arch. Phys. Med. Rehabil. 86, 1007–1013. doi: 10.1016/j.apmr.2004.08.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Sossi, V., de La Fuente-Fernandez, R., Schulzer, M., Troiano, A. R., Ruth, T. J., and Stoessl, A. J. (2007). Dopamine transporter relation to dopamine turnover in Parkinson's disease: a positron emission tomography study. Ann. Neurol. 62, 468–474. doi: 10.1002/ana.21204

PubMed Abstract | CrossRef Full Text | Google Scholar

Sossi, V., Dinelle, K., Topping, G. J., Holden, J. E., Doudet, D., Schulzer, M., et al. (2009). Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study. J. Neurochem. 109, 85–92. doi: 10.1111/j.1471-4159.2009.05904.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., and Goedert, M. (1997). Alpha-synuclein in Lewy bodies. Nature 388, 839–840. doi: 10.1038/42166

PubMed Abstract | CrossRef Full Text | Google Scholar

Spivey, A. (2011). Rotenone and Paraquat Linked to Parkinson's Disease Human Exposure Study Supports Years of Animal Studies. Environ. Health Perspect. 119, A259–A259. doi: 10.1289/ehp.119-a259a

PubMed Abstract | CrossRef Full Text | Google Scholar

Springer, W., Hoppe, T., Schmidt, E., and Baumeister, R. (2005). A Caenorhabditis elegans Parkin mutant with altered solubility couples Synuclein aggregation to proteotoxic stress. Hum. Mol. Genet. 14, 3407–3423. doi: 10.1093/hmg/ddi371

PubMed Abstract | CrossRef Full Text | Google Scholar

Sulston, J., Dew, M., and Brenner, S. (1975). Dopaminergic neurons in the nematode Caenorhabditis elegans. J. Comp. Neurol. 163, 215–226. doi: 10.1002/cne.901630207

PubMed Abstract | CrossRef Full Text | Google Scholar

Suo, S., Sasagawa, N., and Ishiura, S. (2003). Cloning and characterization of a Caenorhabditis elegans D2-like dopamine receptor. J. Neurochem. 86, 869–878. doi: 10.1046/j.1471-4159.2003.01896.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Takeda, A., Sotogaku, N., and Oku, N. (2003). Influence of manganese on the release of neurotransmitters in rat striatum. Brain Res. 965, 279–282. doi: 10.1016/S0006-8993(02)04157-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Tanner, C. M., Kamel, F., Ross, G. W., Hoppin, J. A., Goldman, S. M., Korell, M., et al. (2010). Rotenone, Paraquat and Parkinson's Disease (PD). Ann. Neurol. 68:S17. doi: 10.1289/ehp.1002839

CrossRef Full Text

Tanner, C. M., Kamel, F., Ross, G. W., Hoppin, J. A., Goldman, S. M., Korell, M., et al. (2011). Rotenone, Paraquat, and Parkinson's Disease. Environ. Health Perspect. 119, 866–872. doi: 10.1289/ehp.1002839

PubMed Abstract | CrossRef Full Text | Google Scholar

Taylor, T. N., Greene, J. G., and Miller, G. W. (2010). Behavioral phenotyping of mouse models of Parkinson's disease. Behav. Brain Res. 211, 1–10. doi: 10.1016/j.bbr.2010.03.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Thiele, S. L., Warre, R., and Nash, J. E. (2012). Development of a unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's disease. J. Vis. Exp. pii:3234. doi: 10.3791/3234

CrossRef Full Text

Tissenbaum, H. A. (2015). Using C. elegans for aging research. Invertebr. Reprod. Dev. 59, 59–63. doi: 10.1080/07924259.2014.940470

PubMed Abstract | CrossRef Full Text | Google Scholar

Torres, E. M., and Dunnett, S. B. (2012). “6-OHDA Lesion Models of Parkinson's Disease in the Rat,” in Animal Models of Movement Disorders, Vol. I, eds E. L. Lane and S. B. Dunnett (Totowa, NJ: Humana Press), 267–279.

Google Scholar

Toth, M. L., Melentijevic, I., Shah, L., Bhatia, A., Lu, K., Talwar, A., et al. (2012). Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. J. Neurosci. 32, 8778–8790. doi: 10.1523/JNEUROSCI.1494-11.2012

PubMed Abstract | CrossRef Full Text | Google Scholar

Trempe, J. F., and Fon, E. A. (2013). Structure and function of Parkin, PINK1, and DJ-1, the three musketeers of neuroprotection. Front. Neurol4:38. doi: 10.3389/fneur.2013.00038

PubMed Abstract | CrossRef Full Text | Google Scholar

Trinh, J., and Farrer, M. (2013). Advances in the genetics of Parkinson disease. Nat. Rev. Neurol. 9, 445–454. doi: 10.1038/nrneurol.2013.132

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsunoda, M. (2006). Recent advances in methods for the analysis of catecholamines and their metabolites. Anal. Bioanal. Chem. 386, 506–514. doi: 10.1007/s00216-006-0675-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Uhl, G. R. (1998). Hypothesis: the role of dopaminergic transporters in selective vulnerability of cells in Parkinson's disease. Ann. Neurol. 43, 555–560. doi: 10.1002/ana.410430503

PubMed Abstract | CrossRef Full Text | Google Scholar

Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M., Harvey, K., Gispert, S., et al. (2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158–1160. doi: 10.1126/science.1096284

PubMed Abstract | CrossRef Full Text | Google Scholar

VanDuyn, N., Settivari, R., Levora, J., Zhou, S. Y., Unrine, J., and Nass, R. (2013). The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration. J. Neurochem. 124, 147–157. doi: 10.1111/jnc.12072

PubMed Abstract | CrossRef Full Text | Google Scholar

VanDuyn, N., Settivari, R., Wong, G., and Nass, R. (2010). SKN-1/Nrf2 Inhibits Dopamine Neuron Degeneration in a Caenorhabditis elegans Model of Methylmercury Toxicity. Toxicol. Sci. 118, 613–624. doi: 10.1093/toxsci/kfq285

PubMed Abstract | CrossRef Full Text | Google Scholar

van Ham, T. J., Thijssen, K. L., Breitling, R., Hofstra, R. M. W., Plasterk, R. H. A., and Nollen, E. A. A. (2008). C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genet. 4:e1000027. doi: 10.1371/journal.pgen.1000027

PubMed Abstract | CrossRef Full Text | Google Scholar

Varcin, M., Bentea, E., Michotte, Y., and Sarre, S. (2012). Oxidative stress in genetic mouse models of Parkinson's disease. Oxid. Med. Cell. Longev. 2012:624925. doi: 10.1155/2012/624925

PubMed Abstract | CrossRef Full Text | Google Scholar

Vayndorf, E. M., Scerbak, C., Hunter, S., Neuswanger, J. R., Toth, M., Parker, J. A., et al. (2016). Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis. NPJ Aging Mech. Dis. 2:16001. doi: 10.1038/npjamd.2016.1

PubMed Abstract | CrossRef Full Text | Google Scholar

Ved, R., Saha, S., Westlund, B., Perier, C., Burnam, L., Sluder, A., et al. (2005). Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of alpha-synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J. Biol. Chem. 280, 42655–42668. doi: 10.1074/jbc.M505910200

PubMed Abstract | CrossRef Full Text | Google Scholar

Venderova, K., Kabbach, G., Abdel-Messih, E., Zhang, Y., Parks, R. J., Imai, Y., et al. (2009). Leucine-rich repeat kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease. Hum. Mol. Genet. 18, 4390–4404. doi: 10.1093/hmg/ddp394

PubMed Abstract | CrossRef Full Text | Google Scholar

Vidal-Gadea, A. G., and Pierce-Shimomura, J. T. (2012). Conserved role of dopamine in the modulation of behavior. Commun. Integr. Biol. 5, 440–447. doi: 10.4161/cib.20978

PubMed Abstract | CrossRef Full Text | Google Scholar

Vidal-Gadea, A., Topper, S., Young, L., Crisp, A., Kressin, L., Elbel, E., et al. (2011). Caenorhabditis elegans selects distinct crawling and swimming gaits via dopamine and serotonin. Proc. Natl. Acad. Sci. U.S.A. 108, 17504–17509. doi: 10.1073/pnas.1108673108

PubMed Abstract | CrossRef Full Text | Google Scholar

Visanji, N. P., Brotchie, J. M., Kalia, L. V., Koprich, J. B., Tandon, A., Watts, J. C., et al. (2016). α-Synuclein-Based Animal Models of Parkinson's Disease: challenges and opportunities in a New Era. Trends Neurosci. 39, 750–762. doi: 10.1016/j.tins.2016.09.003

PubMed Abstract | CrossRef Full Text | Google Scholar

Vitte, J., Traver, S., Maués De Paula, A., Lesage, S., Rovelli, G., Corti, O., et al. (2010). Leucine-Rich Repeat Kinase 2 is associated with the endoplasmic reticulum in dopaminergic neurons and accumulates in the core of lewy bodies in Parkinson Disease. J. Neuropathol. Exp. Neurol. 69, 959–972. doi: 10.1097/NEN.0b013e3181efc01c

PubMed Abstract | CrossRef Full Text | Google Scholar

Wahlby, C., Conery, A. L., Bray, M. A., Kamentsky, L., Larkins-Ford, J., Sokolnicki, K. L., et al. (2014). High- and low-throughput scoring of fat mass and body fat distribution in C. elegans. Methods 68, 492–499. doi: 10.1016/j.ymeth.2014.04.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Z., and Sherwood, D. R. (2011). Dissection of Genetic Pathways in C. elegans. Methods Cell Biol. 106, 113–157. doi: 10.1016/B978-0-12-544172-8.00005-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Warner, T. T., and Schapira, A. H. (2003). Genetic and environmental factors in the cause of Parkinson's disease. Anna. Neurol. 53(Suppl. 3), S16–S23; Discussion S23–S15. doi: 10.1002/ana.10487

PubMed Abstract | CrossRef Full Text | Google Scholar

Weinshenker, D., Garriga, G., and Thomas, J. H. (1995). Genetic and pharmacological analysis of neurotransmitters controlling egg laying in C. elegans. J. Neurosci. 15, 6975–6985.

PubMed Abstract | Google Scholar

West, A. B., Moore, D. J., Biskup, S., Bugayenko, A., Smith, W. W., Ross, C. A., et al. (2005). Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc. Natl. Acad. Sci. U.S.A. 102, 16842–16847. doi: 10.1073/pnas.0507360102

PubMed Abstract | CrossRef Full Text | Google Scholar

White, J. G., Southgate, E., Thomson, J. N., and Brenner, S. (1986). The structure of the nervous-system of the Nematode Caenorhabditis-Elegans. Philos. Trans. R. Soc. Lond. B Biol. Sci. 314, 1–340. doi: 10.1098/rstb.1986.0056

PubMed Abstract | CrossRef Full Text | Google Scholar

Whitworth, A. J. (2011). Drosophila models of Parkinson's disease. Adv. Genet. 73, 1–50. doi: 10.1016/b978-0-12-380860-8.00001-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Wise, R. A. (2004). Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494. doi: 10.1038/nrn1406

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, L., and Pu, J. (2016). Alpha-Synuclein in Parkinson's Disease: from Pathogenetic Dysfunction to Potential Clinical Application. Parkinsons Dis. 2016:1720621. doi: 10.1155/2016/1720621

PubMed Abstract | CrossRef Full Text | Google Scholar

Xu, T., Li, P., Wu, S., Lei, L., and He, D. (2017). Tris(2-chloroethyl) phosphate (TCEP) and tris(2-chloropropyl) phosphate (TCPP) induce locomotor deficits and dopaminergic degeneration in Caenorhabditis elegans. Toxicol. Res. 6, 63–72. doi: 10.1039/C6TX00306K

CrossRef Full Text | Google Scholar

Yao, C., El Khoury, R., Wang, W., Byrd, T. A., Pehek, E. A., Thacker, C., et al. (2010a). LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiol. Dis. 40, 73–81. doi: 10.1016/j.nbd.2010.04.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, C., El Khoury, R., Wang, W., Byrd, T. A., Pehek, E. A., Thacker, C., et al. (2010b). LRRK2-mediated neurodegeneration and dysfunction of dopaminergic neurons in a Caenorhabditis elegans model of Parkinson's disease. Neurobiol. Dis. 40, 73–81. doi: 10.1016/j.nbd.2010.04.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, C., Johnson, W. M., Gao, Y., Wang, W., Zhang, J., Deak, M., et al. (2013). Kinase inhibitors arrest neurodegeneration in cell and C. elegans models of LRRK2 toxicity. Hum. Mol. Genet. 22, 328–344. doi: 10.1093/hmg/dds431

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, S. C., Hart, A. D., and Terzella, M. J. (2013). An evidence-based osteopathic approach to Parkinson disease. Osteopathic Family Physic. 5, 96–101. doi: 10.1016/j.osfp.2013.01.003

CrossRef Full Text | Google Scholar

Yen, K., Le, T. T., Bansal, A., Narasimhan, S. D., Cheng, J. X., and Tissenbaum, H. A. (2010). A comparative study of fat storage quantitation in nematode Caenorhabditis elegans using label and label-free methods. PLoS ONE 5:e12810. doi: 10.1371/journal.pone.0012810

PubMed Abstract | CrossRef Full Text | Google Scholar

Yue, Z., and Lachenmayer, M. L. (2011). Genetic LRRK2 models of Parkinson's disease: dissecting the pathogenic pathway and exploring clinical applications. Mov. Disord. 26, 1386–1397. doi: 10.1002/mds.23737

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, S., Wang, Z., and Klaunig, J. E. (2013). Caenorhabditis elegans neuron degeneration and mitochondrial suppression caused by selected environmental chemicals. Int. J. Biochem. Mol. Biol. 4, 191–200. Available online at: http://ijbmb.org/files/ijbmb1309002.pdf

PubMed Abstract | Google Scholar

Zhu, J. H., Gusdon, A. M., Cimen, H., Van Houten, B., Koc, E., and Chu, C. T. (2012). Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2. Cell Death Dis. 3, e312. doi: 10.1038/cddis.2012.46

PubMed Abstract | CrossRef Full Text | Google Scholar

Zimprich, A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M., Lincoln, S., et al. (2004). Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44, 601–607. doi: 10.1016/j.neuron.2004.11.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: Parkinson's disease (PD), Caenorhabditis elegans (C. elegans), behavioral phenotyping, dopamine, pathological markers

Citation: Maulik M, Mitra S, Bult-Ito A, Taylor BE and Vayndorf EM (2017) Behavioral Phenotyping and Pathological Indicators of Parkinson's Disease in C. elegans Models. Front. Genet. 8:77. doi: 10.3389/fgene.2017.00077

Received: 10 April 2017; Accepted: 22 May 2017;
Published: 13 June 2017.

Edited by:

Elena G. Pasyukova, Institute of Molecular Genetics of Russian Academy of Sciences, Russia

Reviewed by:

Jeremy Michael Van Raamsdonk, Van Andel Institute, United States
Srinivas Ayyadevara, Central Arkansas Veterans Healthcare System, United States
Michael Wink, Heidelberg University, Germany

Copyright © 2017 Maulik, Mitra, Bult-Ito, Taylor and Vayndorf. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Elena M. Vayndorf, evayndorf@alaska.edu

These authors have contributed equally to this work.