About this Research Topic
Clathrin-mediated endocytosis (CME) is a fundamental process in which cargo molecules are internalized from the cell surface, packaged into vesicles and trafficked within the cell. In keeping with cargo diversity, CME has different physiological functions, from molecule uptake, receptor internalization, signal transduction to synaptic vesicle recycling. Clathrin is also essential in intracellular processes, of several endomembrane systems which consists of an array of organelles including the endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), trans Golgi Network (TGN), early and late endosomes, lysosomes, endocytic recycling compartment and different domains of plasma membrane.
Several proteins and regulatory elements are involved in the pathway, polymerizing the clathrin lattice, promoting the formation of clathrin-coated vesicles, triggering vesicle scission, functioning as scaffolding proteins, removing the clathrin coat or sorting and transporting membrane proteins within the cell.
Diseases associated with defective membrane traffic collectively manifest in all tissues and organ systems, with some affecting multiple systems and others restricted to one tissue type or organ. Diseases most often arise from mutation that cause loss of expression or function of transport machinery components.
CME and the involved proteins play important functions in most cells, but are particularly essential and important for neural functions. Then, it is not surprising that dysfunctions or dysregulations of the pathway are common hallmarks of several neurological diseases. Recent data showed that mayor neurodegenerative diseases are strongly associated with defects in membrane traffic, particularly within the endosomal system.
Further, several genes, coding for proteins involved in processes that are closely linked to CME and related intracellular trafficking, have been described as associated, candidate or susceptibility genes in neurological and psychiatric disorders. As examples, variants in PICALM or in BIN1, key components of the CME machinery, have been described as risk factors for late-onset Alzheimer's disease. Additionally, deficiency in VPS26 e VPS35, two subunits of the retromer complex for endosomal recycling has been observed in AD patiens. Parkinson's disease is also strongly associated with defective endocytic traffic including mutations in genes like LRRK2, DNAJC13, DNAJC6, GAK, SYNJ1, implicated in the clathrin-mediated synaptic vesicle cycle. Genetic association studies have demonstrated a link between schizophrenia and mutations in genes encoding for proteins that directly interact with or are functionally linked to clathrin-mediated pathways, such as STON2, CLINT1, DTNBP1, DISC1. Adaptinopathies are a new class of neurocutaneous and neurometabolic disorder affecting intracellular trafficking, mediated by clathrin-coated vesicles and their assembly requires adaptor protein complexes. Some of these genetic disorders also display a neurological phenotype, like MEDNIK syndrome and Pettigrew syndrome caused respectively by AP1S1 by AP1S2 mutations. Mutations in DNM2, a GTPase involved in CME, have been implicated in hereditary disorders of the peripheral nervous system, like Charcot Marie Tooth disease. Mutations in the ALS2 gene, in a recessive form of juvenile amyotrophic lateral sclerosis, deregulate early endosome maturation and cargo sorting.
To provide a more comprehensive overview of the role of CME and related intracellular trafficking in neurological and psychiatric diseases, in this special issue we invite researchers and clinicians to submit any type of contribution (original research manuscripts, reviews and perspectives) concerning basic science studies on human neuropathologies, in which CME and related intracellular trafficking are involved.
Contributions on animal and cellular models depicting the role of CME and related intracellular trafficking in neurological and psychiatric disorders, genetic studies on CME-related neurological and psychiatric disorders and therapeutic strategies in CME-related neuropathologies are also welcome.
Keywords: Clathrin-mediated endocytosis (CME), clathrin coated vesicles, intracellular trafficking, neurological disorders, psychiatric disorders
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