A Striatal-Enriched Intronic GPCR Modulates Huntingtin Levels and Toxicity

Elife. 2015 Mar 4;4:e05449. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Cells, Cultured
  • Corpus Striatum / cytology
  • Corpus Striatum / metabolism*
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / physiology
  • Female
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Introns*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Confocal
  • Motor Activity / genetics
  • Motor Activity / physiology
  • Mutation
  • Psychomotor Performance / physiology
  • RNA Interference
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

  • Gpr52 protein, mouse
  • Receptors, G-Protein-Coupled
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse