This scientific commentary refers to ‘Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes’, by Song et al. (doi:10.1093/brain/awy081). Huntington’s disease is a fatal inherited neurodegenerative disorder that is caused by an expanded polyglutamine tract in the N-terminal region of huntingtin (HTT). It is the most common polyglutamine disease, with a prevalence of 4–10 per 100 000. The average age of onset is 40 years, and death often occurs within 15–20 years. Huntington’s disease is characterized by the selective degeneration of medium spiny neurons in the striatum followed by widespread degeneration as the disease progresses. The progressive dysfunction and degeneration of neurons in the brain cause significant motor impairment as well as cognitive and behavioural decline. As a result, Huntington’s disease places a tremendous physical, psychological, as well as financial burden on the patient, their families, and caregivers. Currently, a number of treatments are being developed for Huntington’s disease, which include antisense oligonucleotides and adeno-associated virus (AAV)-mediated delivery of RNAi and CRISPR/Cas9 to reduce the level of mutant huntingtin (mHTT) (Kordasiewicz et al., 2012; Yang et al., 2017). While these are effective strategies, the delivery of these compounds to the brain is quite challenging and requires injection directly into the CNS. In this issue of Brain, Song and co-workers present an alternative therapeutic strategy, demonstrating the potential of pharmaceutically blocking G-protein coupled receptor 52 (Gpr52) for reducing mHTT levels as a treatment for Huntington’s disease (Song et al., 2018). Gpr52 is expressed exclusively in the brain and is enriched in the medium spiny neurons of the striatum (Komatsu et al., 2014) (Fig. 1A). The authors previously identified Gpr52 as a modulator of mHTT levels in an siRNA screen (Yao et al., 2015). They found that activation of Gpr52 leads to HTT translocation to the endoplasmic reticulum (ER), where it can escape proteasomal degradation, leading to HTT stabilization (Fig. 1B). The enrichment of Gpr52 in medium spiny neurons and the selective degeneration of the striatum in Huntington’s disease, in addition to G-protein coupled receptors (GPCRs) being particularly attractive drug targets, made Gpr52 an appealing target for further investigation. Song et al. used an extremely comprehensive approach to establish a clear role for Gpr52 in Huntington’s disease. First, the authors crossed a Gpr52 mouse knockout (Gpr52 KO) to a well-established and well-characterized Huntington’s disease mouse model, Hdh140Q, in order to determine the effect of Gpr52 KO in the context of Huntington’s disease (Fig. 1C). Loss of Gpr52 significantly rescued disease-associated phenotypes such as motor impairment and anxiety. Importantly, knockout of Gpr52 reduced mHTT levels in the brain, and the effect was specific to the striatum—levels of mHTT were unchanged in other brain regions. Figure 1 View largeDownload slide Proposed role of Gpr52 in the modulation of HTT levels and experimental design to investigate potential of Gpr52 as a druggable target for the treatment of Huntington’s disease. (A) Gpr52 is enriched in the medium spiny neurons of the striatum. (B) Schematic of the proposed role of Gpr52 in modulating HTT levels in medium spiny neurons. Gpr52 activation leads to an increase in cAMP levels. This increase in cAMP levels activates a guanine nucleotide exchange factor (GEF), which then activates Rab39B. Rab39B co-localizes with HTT and translocates it to the ER, where it cannot be degraded by the proteasome (adapted from Yao et al., 2015). (C) Experimental design for Gpr52 genetic knockout experiments. The Huntington’s disease mouse model Hdh140Q was crossed to Gpr52 KO mice, and motor function and behavioural phenotypes were assessed using multiple assays. (D) Experimental design for striatal expression of Gpr52 in Gpr52 KO/Hdh140Q mice. AAV expressing human Gpr52 was injected into the left and right striata of 10.5-month-old mice. Behavioural tests were performed 3 and 4.5 months after injection, and animals were sacrificed at age 16 months. (E) Experimental design for pharmacological inhibition of Gpr52 with E7. Hdh140Q mice aged 8.5 months were injected with a dose of E7 for nine consecutive days, then immediately subjected to behavioural tests and sacrificed for histological analysis. Figure 1 View largeDownload slide Proposed role of Gpr52 in the modulation of HTT levels and experimental design to investigate potential of Gpr52 as a druggable target for the treatment of Huntington’s disease. (A) Gpr52 is enriched in the medium spiny neurons of the striatum. (B) Schematic of the proposed role of Gpr52 in modulating HTT levels in medium spiny neurons. Gpr52 activation leads to an increase in cAMP levels. This increase in cAMP levels activates a guanine nucleotide exchange factor (GEF), which then activates Rab39B. Rab39B co-localizes with HTT and translocates it to the ER, where it cannot be degraded by the proteasome (adapted from Yao et al., 2015). (C) Experimental design for Gpr52 genetic knockout experiments. The Huntington’s disease mouse model Hdh140Q was crossed to Gpr52 KO mice, and motor function and behavioural phenotypes were assessed using multiple assays. (D) Experimental design for striatal expression of Gpr52 in Gpr52 KO/Hdh140Q mice. AAV expressing human Gpr52 was injected into the left and right striata of 10.5-month-old mice. Behavioural tests were performed 3 and 4.5 months after injection, and animals were sacrificed at age 16 months. (E) Experimental design for pharmacological inhibition of Gpr52 with E7. Hdh140Q mice aged 8.5 months were injected with a dose of E7 for nine consecutive days, then immediately subjected to behavioural tests and sacrificed for histological analysis. The rescue of Huntington’s disease-associated symptoms and reduction of mHTT in Gpr52 KO/Hdh140Q mice suggests that loss of Gpr52 mediates these effects. To confirm that the effects were Gpr52-dependent, the authors next performed the inverse experiment, in which they delivered Gpr52 to the striatum by injecting AAV expressing human Gpr52 (hGpr52) into Gpr52 KO/Hdh140Q mice (Fig. 1D). Expression of Gpr52 in the striatum caused the mice to develop behavioural deficits and an increase in soluble mHTT levels. These results suggest that Gpr52 mediates Huntington’s disease-associated phenotypes as well as regulates mHTT levels in vivo. By knocking out and then restoring mHTT expression in the Hdh140Q mouse brain, Song et al. provide compelling evidence for Gpr52’s role in the modulation of mHTT levels as well as Huntington’s disease behavioural phenotypes. However, the highlight of the study is the pharmacological inhibition of Gpr52 by a small molecule, ‘E7’. Song et al. performed a screen to identify novel antagonists of Gpr52, and found E7 to be an effective inhibitor of Gpr52. The authors delivered E7 to the brains of Hdh140Q mice via intracerebroventricular injections for nine consecutive days, then performed behavioural tests immediately after and harvested tissue for histological analysis (Fig. 1E). Strikingly, inhibition of Gpr52 by E7 had immediate effects on mHTT levels and motor performance. More importantly, E7 injection into symptomatic mice demonstrated that inhibition of Gpr52 is able to reverse Huntington’s disease symptoms after onset. These findings were replicated in multiple model systems, including Drosophila and patient induced pluripotent stem cell-derived striatal neurons. Together, these results demonstrate the tremendous potential of Gpr52 inhibition as a treatment for Huntington’s disease. Glossary G-protein coupled receptors (GPCRs): Cell surface receptors that transduce extracellular stimuli into intracellular signals. Because of their surface localization and involvement in numerous key cellular processes as well as diseases, GPCRs are a major target for drug discovery and development. Hdh140Q model: A commonly used mouse model of Huntington’s disease that was developed by inserting a chimeric mouse/human huntingtin exon 1 containing 140 CAG repeats into the mouse huntingtin gene (Htt). This model expresses mHTT in the appropriate genomic and protein context. The authors thus used three complementary approaches to establish a clear role for Gpr52 in Huntington’s disease, and to establish Gpr52 as a promising target for therapeutic intervention. However, some questions remain. First, as with most treatments being developed for this disorder, Gpr52-mediated reduction of mHTT is non-allele-specific and results in the reduction of both the mutant and wild-type protein. Huntingtin is an important protein that is involved in numerous processes (Cattaneo et al., 2005). Non-allele-specific silencing of huntingtin has been shown to lead to transcriptional changes and to alter many of these processes (Drouet et al., 2009). Second, while Song et al. showed that administration of E7 reduced mHTT levels and rescued disease-associated phenotypes, it is unclear if these effects persist after administration, or if Gpr52 must be continuously inhibited. One study suggests that Gpr52 plays a role in dopaminergic and glutamatergic transmission, and that knockout of Gpr52 in mice results in psychosis-like behaviours (Komatsu et al., 2014). Therefore, long-term inhibition of Gpr52 must be further examined. And of course the biggest question that comes to mind is, how well will these findings translate to humans? The Hdh140Q mouse successfully models the age-dependent accumulation and aggregation of mHTT, as well as the progressive development of behavioural and locomotor abnormalities. However, this model does not perfectly recapitulate the severity of human Huntington’s disease. Compared with humans, Hdh140Q mice have a relatively mild phenotype, with a slow progression. Hdh140Q mice have a normal lifespan, and loss of striatal neurons and striatal atrophy are not apparent until 2 years of age. A number of studies have found that striatal atrophy is present years before diagnosable symptoms appear (Bates et al., 2015). Song et al. demonstrate the ability of Gpr52 inhibition to reverse Huntington’s disease-associated phenotypes in 8.5-month-old Hdh140Q mice. This suggests that Gpr52 inhibition and subsequent reduction of mHTT levels might be able to reverse the cellular dysfunction that is caused by mHTT. However, because of the limitations of the Hdh140Q mouse model, the authors have not shown whether Gpr52 inhibition has an effect on neuronal survival or striatal degeneration. In thinking about the next steps for this promising line of research, one major hurdle to overcome is that the authors’ current method of E7 delivery is no less challenging than other treatment methods (e.g. antisense oligonucleotides or viral delivery of RNA interference). A small molecule, orally bioavailable drug would be ideal for treating Huntington’s disease. It is currently unknown whether E7 or any other Gpr52 antagonist can cross the blood–brain barrier. Moving forward with Gpr52 as a therapeutic target will require identifying or designing a small molecule inhibitor of Gpr52 that can do this, and then showing that the therapy would be less expensive, more effective, easier to deliver, and/or better tolerated than other therapies that are further along in their development. In summary, the findings of Song et al. are extremely promising and provide a strong basis for Gpr52 as an entry point for Huntington’s disease drug discovery. Several recent studies have shown that transcellular spreading of mutant huntingtin may contribute to Huntington’s disease pathogenesis (Pecho-Vrieseling et al., 2014; Pearce et al., 2015). If spreading begins in the striatum, then reducing the levels of mHTT specifically in medium spiny neurons would be an effective way to stop the spread of mHTT in its tracks and halt progression of the disease. References Bates GP , Dorsey R , Gusella JF , Hayden MR , Kay C , Leavitt BR , et al. Huntington disease . Nat Rev Dis Primers 2015 ; 23 : 15005 . Google Scholar CrossRef Search ADS Cattaneo E , Zuccato C , Tartari M . Normal huntingtin function: an alternative approach to Huntington’s disease . Nat Rev Neurosci 2005 ; 6 : 919 – 30 . Google Scholar CrossRef Search ADS PubMed Drouet V , Perrin V , Hassig R , Dufour N , Auregan G , Alves S , et al. Sustained effects of nonallele-specific Huntingtin silencing . Ann Neurol 2009 ; 65 : 276 – 85 . Google Scholar CrossRef Search ADS PubMed Komatsu H , Maruyama M , Yao S , Shinohara T , Sakuma K , Imaichi S , et al. Anatomical transcriptome of G protein-coupled receptor leads to the identification of a novel therapeutic candidate GPR52 for psychiatric disorders . PLos One 2014 ; 9 : e90134 . Google Scholar CrossRef Search ADS PubMed Kordasiewicz HB , Stanek LM , Wancewicz EV , Mazur C , McAlonis MM , Pytel KA , et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis . Neuron 2012 ; 74 : 1031 – 44 . Google Scholar CrossRef Search ADS PubMed Pearce MM , Spartz EJ , Hong W , Luo L , Kopito RR . Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain . Nat Commun 2015 ; 6 : 6768 . Google Scholar CrossRef Search ADS PubMed Pecho-Vrieseling E , Rieker C , Fuchs S , Bleckmann D , Esposito MS , Botta P , et al. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons . Nat Neurosci 2014 ; 17 : 1064 – 72 . Google Scholar CrossRef Search ADS PubMed Song H , Li H , Guo S , Pan Y , Fu Y , Zhou Z , et al. Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes . Brain 2018 ; 141 : 1782 – 98 . Yang S , Chang R , Yang H , Zhao T , Hong Y , Kong HE , et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease . J Clin Invest 2017 ; 127 : 2719 – 24 . Google Scholar CrossRef Search ADS PubMed Yao Y , Al-Ramahi I , Sun X , Li B , Hou J , Difiglia M , et al. A striatal-enriched intronic GPRC modulates huntingtin levels and toxicity . Elife 2015 ; 4 : 4 . Google Scholar CrossRef Search ADS © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Brain – Oxford University Press
Published: May 25, 2018
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