A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity
- Fudan University, China
- Baylor College of Medicine, United States
- Massachusetts General Hospital, United States
- Novartis Institutes for Biomedical Research, United States
- Zhejiang University, China
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.
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Ethics
Animal experimentation: The mouse experiments were carried out following the general guidelines published by the Association for Assessment and Accreditation of Laboratory Animal Care. The Animal Care and Use Committee of the School of Medicine at Fudan University approved the protocol used in animal experiments (Approval #20140904).
Human subjects: The study involves obtaining dermal fibroblasts from human patients. The study was approved by the ethic community of IBS at Fudan University (No.28), strictly following their general guidelines for experiments involving human subjects. Verbal and written informed consent, and the consent to publish, were obtained from all patients.
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© 2015, Yao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity
eLife 4:e05449.
https://doi.org/10.7554/eLife.05449
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