A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity

  • Yao Y
  • Cui X
  • Al-Ramahi I
  • et al.
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Abstract

Huntington's disease (HD) represents an important model for neurodegenerative disorders and proteinopathies. It is mainly caused by cytotoxicity of the mutant huntingtin protein (Htt) with an expanded polyQ stretch. While Htt is ubiquitously expressed, HD is characterized by selective neurodegeneration of the striatum. Here we report a striatal-enriched orphan G protein-coupled receptor(GPCR) Gpr52 as a stabilizer of Htt in vitro and in vivo. Gpr52 modulates Htt via cAMP-dependent but PKA independent mechanisms. Gpr52 is located within an intron of Rabgap1l, which exhibits epistatic effects on Gpr52-mediated modulation of Htt levels by inhibiting its substrate Rab39B, which co-localizes with Htt and translocates Htt to the endoplasmic reticulum. Finally, reducing Gpr52 suppresses HD phenotypes in both patient iPS-derived neurons and in vivo Drosophila HD models. Thus, our discovery reveals modulation of Htt levels by a striatal-enriched GPCR via its GPCR function, providing insights into the selective neurodegeneration and potential treatment strategies.Huntington's disease is an inherited disorder of the central nervous system. Symptoms typically begin between the ages of 30 and 50, and initially include clumsiness and uncontrollable movements, as well as personality changes and mood swings. Symptoms worsen over time and life expectancy is usually around 10 to 25 years following diagnosis.The disease is caused by a mutation in the ‘huntingtin’ gene, which leads to the production of an abnormal form of ‘huntingtin’ protein. This accumulates inside neurons in a region of the brain called the striatum, which is involved in the control of movement, and destroys them. However, it is not clear why other regions of the brain that also produce the mutant huntingtin protein are not affected.Yao, Cui, Al-Ramahi, Sun et al. have now identified a protein that could explain this phenomenon and open up new therapeutic possibilities for Huntington's disease. The protein, which is called Gpr52, is a receptor located within the outer membrane of neurons, particularly those in the striatum. Reducing the levels of this protein reduced the amount of mutant huntingtin protein that was able to accumulate inside cells grown in culture. Moreover, mice that were genetically engineered to possess a mutant huntingtin gene, but only a single copy of the gene for Gpr52, accumulated less mutant huntingtin in the striatum than mice with two copies of the Gpr52 gene.Further experiments revealed that Gpr52 protects mutant huntingtin from being broken down inside cells: it does this by activating a signaling pathway involving the cellular messenger cAMP. Encouragingly, when genetic techniques were used to reduce Gpr52 synthesis in a fruit fly model of Huntington's disease, the treated flies showed fewer movement impairments than flies that had not been treated. In addition, reduced levels of Gpr52 were observed to lead to dramatic protective effects in neurons derived from the stem cells of a patient with Huntington's disease.The fact that Gpr52 is located on the surface of neurons means that it might be possible to design drugs that can block its activity and thus reduce accumulation of mutant huntingtin. Such a treatment would be the first to target the causal mechanism behind Huntington's disease, rather than simply addressing the symptoms. The strategy could also be relevant to Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders in which death of neurons is triggered by abnormal accumulation or aggregation of proteins.

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Yao, Y., Cui, X., Al-Ramahi, I., Sun, X., Li, B., Hou, J., … Lu, B. (2015). A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. ELife, 4. https://doi.org/10.7554/elife.05449

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