Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease, typically showing abnormal movement (predominantly chorea), cognitive impairment, and psychiatric features. The average age at onset is 40 years, followed by an inexorable clinical deterioration and average survival of 15 to 20 years (Ghosh and Tabrizi, 2018). Juvenile HD begins before the age of 21 and then worsens rapidly, usually eventuating in death 10 years or so from the motor onset (Quigley, 2017). HD prevalence fluctuates with up to a 10fold difference across the world (Rawlins et al., 2016). The prevalence studies show a worldwide prevalence of 2.7 per 100,000 with the highest rates in Western countries (Pringsheim et al., 2012; Rawlins et al., 2016). Current remedies are limited to symptomatic treatments, such as quetiapine in the treatment of behavioral symptoms of HD (Alpay and Koroshetz, 2006), as no treatment has been demonstrated to forestall or decelerate the disease progression.

Huntington’s disease pathology is characterized by abnormal protein aggregation and its spread in brain, as seen in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS; Boland et al., 2018). This is attributed to an expanded cytosine-adenine-guanine (CAG) repeat in exon 1 of the huntingtin gene (HTT) on chromosome 4. This genetic change encodes an abnormally long polyglutamine (polyQ) sequence near the amino terminus of the huntingtin protein (HTT). This protein has toxic features with dysfunction and death of neurons. Striatal GABAergic medium spiny neurons (MSNs) are particularly vulnerable to mutant huntingtin-induced toxicity, while HD has been recognized as a disorder of the entire body and brain (Bates et al., 2015). Its genetic pathogenesis allows for diagnostic and predictive testing for the disease. Furthermore, the genetic certainty of HD enables us to provide appealing genetic models to study disease mechanisms and therapeutic approaches.

Intensive research has provided substantial insights into the pathological mechanisms in HD. Given the monogenic nature of HD in which the pathology is attributed to production of mutant huntingtin protein (mHTT), lowering of mHTT has emerged as a promising therapeutic approach. Clinical trials are currently planned or underway for novel therapeutics for HD, mostly gene silencing or mHTT-lowering medicines aimed at reducing production of the mHTT. However, delivery of these HTT lowering therapies, such as small interference RNAs and antisense oligonucleotides (ASOs), has proven to be a considerable challenge. It needs injection directly into the central nervous system (CNS) that places a great burden on patients. In addition, these agents are difficult to reach the human brain, especially the striatum in which the most striking neuronal loss is observed. Naked siRNAs do not penetrate the blood-brain barrier (BBB) as well as the cell membrane, and therefore need viral vectors to transport siRNA into neurons through bilateral direct injection into the striatum (Chen et al., 2020; Wang et al., 2021). Another critical issue is that human brain is distinctive for its anatomical complexity. Thus, promising findings from animal models do not necessarily lead to successful outcomes in human. Since human brain is approximately 3,000 times larger than mouse brain, any oligonucleotide delivery into the brain would exhibit a totally different pattern of distribution throughout the parenchyma (Pouladi et al., 2013).

G protein-coupled receptors (GPCRs), also known as seven-transmembrane domain receptors, are one of the most widely exploited targets for therapeutics and account for nearly 30% of the Food and Drug Administration (FDA)-approved drug targets. In particular, most neuropharmacological drugs are well known to control GPCR activity in the CNS (Hauser et al., 2017). Among them, GPR52 is an orphan GPCR exclusively expressed in the brain, especially in the striatum (Komatsu et al., 2014), and represents a potential therapeutic target for HD (Komatsu, 2021; Wang et al., 2021). Deletion or knockdown of GPR52 alleviates HD-like phenotypes in the animal models and patient induced pluripotent stem cell (iPSC)-derived neurons (Yao et al., 2015; Song et al., 2018). More recently, highly potent, specific, and BBB-penetrating GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship (SAR) study. Furthermore, these antagonists not only reduce mHTT levels but also ameliorate HD-associated phenotypes in HD mice (Wang et al., 2021). This review will cover the mechanisms of HD pathogenesis, current clinical trials, and innovative approaches that aim to prevent or slow the disease progression.

Huntingtin gene encodes a large protein that is broadly expressed throughout the adult body with the highest level in the brain and has multiple interaction domains (Sharp et al., 1995; Sayer et al., 2005), playing a role as a scaffolding protein that clusters many binding partners (Cattaneo et al., 2005; Zuccato et al., 2010). HTT is localized in the cytoplasm, endosomes (Pal et al., 2006; Atwal et al., 2007), and the nuclear matrix (Atwal et al., 2007). Although wild-type HTT engages distinct signaling events, such as axonal transport, vesicular trafficking, cell division, and transcriptional regulation, and is indispensable for early embryonic development (Bates et al., 2015; Saudou and Humbert, 2016), its normal function remains largely elusive. Deletion of mouse HTT prior to neural development results in embryonic lethal. Conditional deletion of HTT in the forebrain in the early postnatal period leads to a progressive degenerative neuronal phenotype (Dragatsis et al., 2000). However, the depletion fails to cause adult neurodegeneration or animal death at more than 4 months of age, whereas the knockout mice die at 2 months of age of acute pancreatitis owing to the degeneration of pancreatic acinar cells (Wang et al., 2016). These findings imply that wild-type HTT reduction is unlikely to be harmful in adult patients treated with HTT lowering therapies.

Expansion of the CAG repeats of the HTT gene to 40 or more causes the adult onset with a mean age of 40 years, whereas patients with juvenile HD, carrying a mutation with more than 55 CAG repeats, show much more aggressively progression (Bates et al., 2015). The CAG repeat expansion and subsequent outcomes have been confirmed in cultured fibroblasts from HTT mutation carriers (Seong et al., 2005; Reis et al., 2011; HD iPSC Consortium, 2012), up to 15 years before the onset of HD symptoms (Paulsen et al., 2008). The CAG repeat length in HTT determines the degree of severity of the disease and is also a crucial determinant of the rate of HD pathogenesis that leads to the distinctive features of motor dysfunctions. The CAG size accounts for more than 56% of the variation found in the age at motor onset (Gusella et al., 2014). Most of the remaining variation can be attributed to genetic differences among the patients that affect the rate of HD pathogenesis. For instance, TP53, MAP2K6, MAP3K5, GRIN2A, GRIN2B, NPY, NPY2R, and ADORA2A, have been considered as potential genetic modifiers of HD (Gusella et al., 2014). The genome-wide unbiased analyses may provide new clues to disease pathways or processes as therapeutic targets competent for slowing the progression.

As already mentioned, mHTT has an aberrant elongated polyQ tract near the amino terminus. This leads to the accumulation of protein aggregates that initiates a cascade of pathogenic events. The biological and pathological features include transcriptional and synaptic dysfunctions, aberrant axonal trafficking and proteostasis, imperfect nuclear pore complex, oxidative stress, and mitochondrial malfunction (Bates et al., 2015; Grima et al., 2017). The full-length mHTT expression in animal models is well known to elicit HD-like neuropathology and behaviors, including striatal atrophy and motor deficits (Slow et al., 2003). The proteolytic cleavage of the mHTT by endoproteases, including caspases and calpains, is also found to produce N-terminal mHTT fragments that can generate neurotoxicity (Ratovitski et al., 2009; Landles et al., 2010). Indeed, the mHTT fragments have been isolated from HD postmortem brains (Lunkes et al., 2002). Furthermore, the polyQ-containing domain of the HTT protein or exon 1 HTT sufficiently provokes progressive neurological phenotypes in mice (Mangiarini et al., 1996). Intriguingly, CAG repeat length-dependent aberrant splicing of exon 1 HTT yields the pathogenic exon 1 protein (Sathasivam et al., 2013). On the other hand, the CAG-expanded HTT mRNA by itself may be responsible for HD toxicity (Rue et al., 2016). These findings suggest that targeting the leading cause of disease, namely, mutated HTT, could abrogate all these potential underlying pathophysiological mechanisms.

Huntington’s disease is generally diagnosed based on findings from clinical evaluation, patient history (including any family history) and, in most cases, genetic testing for the presence of the CAG expansion in HTT. The characteristic features are motor dysfunction (most typically chorea), cognitive impairment (such as deficits in attention and emotion recognition), and psychiatric symptoms (typically apathy and blunted affect). In some cases, especially if a patient’s family history and genetic testing are inconclusive, brain imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI), can support the diagnosis. As the disease progresses, these scans typically show symmetrical striatal atrophy of the caudate and putamen, a concomitant increase in size of the fluid-filled lateral ventricle, and often, to a lesser degree, atrophy in cerebral cortical gray matter and subcortical white matter. These atrophy patterns do not necessarily indicate HD, because they can occur in other disorders. A person has normal findings on a CT or MRI scan, while showing early symptoms of HD (Bates et al., 2015).

The Unified Huntington’s Disease Rating Scale (UHDRS) is a standardized test used to quantify the severity of HD. This test measures the patient’s abilities in four general areas: motor control, cognitive symptoms, behavioral symptoms, and function in day-to-day life. UHDRS allows us to determine how much of an impact a drug or treatment is having on an individual’s HD (Siesling et al., 1998). The different areas of the rating scale can be administered separately. A UHDRS total motor score (TMS) is strongly supportive of the diagnosis and is formed of 15 items. The different items of the UHDRS-TMS include chorea, dystonia, parkinsonism, motor performance, oculomotor function, and balance (Mestre et al., 2018). Diagnosis of motor onset of manifest HD is currently made based on the UHDRS-TMS (Reilmann and Schubert, 2017). Furthermore, a more extensive series of diagnostic classifications have been proposed by considering results of cognitive function, natural history, and neuroimaging studies. The more formal definitions based on natural history that have been proposed are as follows: a premanifest or presymptomatic stage, followed by a prodromal phase and manifest HD (Reilmann et al., 2014). Initially, a period occurs in which individuals exhibit no clinical symptoms of HD and are therefore termed “presymptomatic,” typically up to 10 to 15 years before the onset. Individuals may then enter the “prodromal” period, during which subtle signs and symptoms are observed. Manifest HD shows slow progression of motor and cognitive impairments, accompanied by chorea often prominent early but plateauing or even diminishing later. Fine motor impairments, such as incoordination, bradykinesia, and rigidity, progress more steadily (Reilmann et al., 2014).

Tremendous advances have been made in understanding the clinical manifestations of HD with the identification of numerous potential therapeutic targets. While a number of clinical trials have been unsuccessful (Bashir, 2019), many more are in progress with the prospect of providing evidence for disease-modifying therapies. Among them, the current trials of mHTT-lowering hold great promise and may open up a new era for HD treatment at the proximal level. On the other hand, delivering ASOs, siRNAs, or genome editing reagents into the CNS is challenging and expensive. Therefore, small molecule drugs that lower mHTT levels are highly desired. GPR52 would be the best target for such small molecule drugs. Accumulating evidence suggests that transcellular spreading of mHTT may cause HD manifestations, as seen in other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases (Boland et al., 2018). If the propagation of mHTT begins in the striatum, decreasing the levels of mHTT exclusively in MSNs would be an effective approach to block its spread and slow the disease progression.

G protein-coupled receptors are located on the cell membrane and regulated by extracellular ligands, making them ideal targets for small molecule compounds. They control myriad physiological responses including neurotransmission, metabolism, hemostasis, reproduction, and immune function (Hauser et al., 2017). GPR52 is an orphan GPCR, though antipsychotic drug reserpine is identified as its surrogate ligand to elicit intracellular cAMP rise, indicating that this receptor is a Gs-coupled receptor. GPR52 is expressed in dopamine D2 receptor (D2R)-expressing MSNs of the basal ganglia, while largely expressed in dopamine D1 receptor (D1R)-expressing neurons in the medial prefrontal cortex (Figure 1). GPR52 represents a promising therapeutic target for the treatment of not only HD but also Parkinson’s disease (Russell et al., 2021), schizophrenia, and several other psychiatric disorders (Komatsu et al., 2014). For instance, GPR52 agonists are well-known to inhibit D2R signaling and activate D1R/NMDA receptors via intracellular cAMP accumulation, demonstrating antipsychotic-like and procognitive effects in rodents (Setoh et al., 2014; Komatsu, 2015; Nishiyama et al., 2017a; Wang et al., 2020).

A series of the druggable GPR52 antagonists have been discovered through approximately ten thousand compounds and subsequent SAR study. Wang et al. (2021) initially discovered compound F11 [(E)-1,7-diphenylhept-4-en-3-one] with IC50 value of approximately 5 μM. F11 consist of an α, β-unsaturated carbonyl group, a linker and terminal aryl-substitutes. Based on this compound, they explored the SAR and produced a novel, specific, and highly potent antagonist, or Comp-43. The SAR study demonstrates that α, β-unsaturated carbonyl group is an essential pharmacophore and the aryl substitutions on the two terminals form a π-π stacking interaction with the residues of GPR52 in the narrow binding cavity, which is consistent with recent findings on the high-resolution structure of human GPR52 (Lin et al., 2020). A computational study by molecular docking with GPR52 crystal structure have demonstrated that GPR52 antagonists enter the same binding site of GPR52 as the agonists, which is consistent with the SAR study (Wang et al., 2021). Thus, structure-based SAR investigation will facilitate the design of selective and potent GPR52 antagonists.

The endogenous ligand for GPR52 remains unknown and may not actually exist. The crystal structure of GPR52 uncovered a non-canonical mechanism of its extracellular loop (ECL2) acting as an internal agonist and accounting for constitutive activity of the receptor (Lin et al., 2020). Intriguingly, GPR52 negative allosteric modulator (NAM) and inverse agonists, including cannabinoid ligands Cannabidiol and O-1918, have been identified so far (Stott et al., 2021). These findings may help design various types of GPR52 modulators.

This review highlights GPR52 as a novel candidate target for HD therapy. However, some questions remain. First, it is unclear if GPR52 must be persistently inhibited. GPR52 knockout mice exhibited no change in body weight, brain morphology, and the travel distance. Meanwhile, they exhibited higher frequency of startle but not prepulse inhibition behaviors when treated with the NMDA receptor antagonist MK-801 (Komatsu, 2015), and enhanced the locomotor-stimulating effect of the ADORA2A antagonist istradefylline (Nishiyama et al., 2017a,b). GPR52 knockout mice also showed the increased time staying in the central region in the open-field test (Komatsu, 2015), as well as the increased novelty-induced locomotor activity (Nishiyama et al., 2017a,b). Taken all together, these findings indicate that GPR52 plays a key role in glutamatergic and dopaminergic synaptic transmissions and persistent GPR52 inhibition may elicit psychiatric manifestations. Second, GPR52-mediated action is non-allele-specific for HTT, leading to the downregulation of both the mutant and wild-type proteins (Wang et al., 2021). HTT serves as an essential protein involved in numerous biological processes. Non-allele-specific lowering of HTT would affect many of these processes. Third, it remains elusive whether inhibition of GPR52 signaling is enough to attenuate the progressive deterioration in HD. GPR52 is localized in the striatopallidal MSNs but not in all MSNs (Komatsu, 2015), which might result in a limited clinical impact (Figure 1).

In the last decade, we have seen a transition from symptomatic therapy to disease-modifying. Hence, the development of clinical and imaging biomarkers will be essential to accelerate the translation of HTT lowering therapies. Many HD pharmacodynamic biomarker candidates have been identified, including electrophysiologic clinical measures, biofluid biomarkers, and functional brain imaging (Weir et al., 2011). At present, only CSF biomarkers are the most useful for tracking disease progression in HTT lowering clinical trials (Byrne et al., 2018). Although neuroimaging techniques, particularly mHTT-specific positron emission tomography (PET) ligands could provide useful biomarkers for direct measurement of mHTT in brain, such ligands have not yet been established. Measurement of disease-associated biomarkers is a crucial element for clinical trial design. A biomarker indicative of neuronal damage or other pathological processes, such as neuroinflammation, will be instrumental for diagnosis, judging therapeutic efficacy, and tracking disease progression. Combination of biomarkers with predictive genetic HD testing can offer an opportunity to start treatment before symptom onset and deter neurodegeneration. We will see further expansion of HTT lowering therapies in the coming years, and much research on HD will refine and expand its goals in search of a treatment.

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HK is employed by Kyowa Pharmaceutical Industry Co., Ltd.

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