2. Academic Validation
  3. A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity

A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity

  • Elife. 2015 Mar 4;4:e05449. doi: 10.7554/eLife.05449.
Yuwei Yao 1,  Xiaotian Cui 1,  Ismael Al-Ramahi 2,  Xiaoli Sun 1,  Bo Li 1,  Jiapeng Hou 1,  Marian Difiglia 3,  James Palacino 4,  Zhi-Ying Wu 5,  Lixiang Ma 6,  Juan Botas 2,  Boxun Lu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
  • 3 MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, United States.
  • 4 Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
  • 5 Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 6 Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China.
PMID: 25738228 DOI: 10.7554/eLife.05449
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.

Keywords

D. melanogaster; GPCR; cyclic AMP; human; human biology; huntington's disease; intron; medicine; mouse; neurodegeneration; neuroscience; polyQ.

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