A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity
Yuwei Yao,
Xiaotian Cui,
Ismael Al-Ramahi,
Xiaoli Sun,
Bo Li,
Jiapeng Hou,
Marian Difiglia,
James Palacino,
Zhi-Ying Wu,
Lixiang Ma,
Juan Botas,
Boxun Lu
Affiliations
Yuwei Yao
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China; Collaborative Innovation Center for Brain Science, Shanghai, China
Xiaotian Cui
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China; Collaborative Innovation Center for Brain Science, Shanghai, China
Ismael Al-Ramahi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Xiaoli Sun
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China; Collaborative Innovation Center for Brain Science, Shanghai, China
Bo Li
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
Jiapeng Hou
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
Marian Difiglia
MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, United States
James Palacino
Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
Zhi-Ying Wu
Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
Lixiang Ma
Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China
Juan Botas
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Boxun Lu
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China; Collaborative Innovation Center for Brain Science, Shanghai, China
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.
