A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity.
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.
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Yuwei
Y
Yao
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Xiaotian
X
Cui
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Ismael
I
Al-Ramahi
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Xiaoli
X
Sun
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Bo
B
Li
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Jiapeng
J
Hou
MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, United States.
Marian
M
Difiglia
Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States.
James
J
Palacino
Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Zhi-Ying
ZY
Wu
Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China.
Lixiang
L
Ma
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
Juan
J
Botas
State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China.
Boxun
B
Lu
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007438:Introns; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009154:Mutation; D011597:Psychomotor Performance / Q000502:physiology; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*
C000592538:Gpr52 protein, mouse; D043562:Receptors, G-Protein-Coupled; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse
D. melanogaster; GPCR; cyclic AMP; human; human biology; huntington's disease; intron; medicine; mouse; neurodegeneration; neuroscience; polyQ