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Yao, Y., Cui, X., Al-Ramahi, I., Sun, X., Li, B., Hou, J., Difiglia, M., Palacino, J., Wu, Z.Y., Ma, L., Botas, J., Lu, B. (2015). A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity.  eLife 4(): e05449.
FlyBase ID
FBrf0227949
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC4372774 (PMC) (EuropePMC)
Related Publication(s)
Personal communication to FlyBase

P{UAS-hHTT.200Q} line.
Botas, 2016.11.17, P{UAS-hHTT.200Q} line. [FBrf0234091]

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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference
    Alleles (7)
    Genes (4)
    Human Disease Models (1)
    Insertions (1)
    Transgenic Constructs (4)