1. Neuroscience

A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity

  1. Yuwei Yao
  2. Xiaotian Cui
  3. Ismael Al-Ramahi
  4. Xiaoli Sun
  5. Bo Li
  6. Jiapeng Hou
  7. Marian Difiglia
  8. James Palacino
  9. Zhi-Ying Wu
  10. Lixiang Ma
  11. Juan Botas
  12. Boxun Lu  Is a corresponding author
  1. Fudan University, China
  2. Baylor College of Medicine, United States
  3. Massachusetts General Hospital, United States
  4. Novartis Institutes for Biomedical Research, United States
  5. Zhejiang University, China
https://doi.org/10.7554/eLife.05449
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  1. Yuwei Yao
  2. Xiaotian Cui
  3. Ismael Al-Ramahi
  4. Xiaoli Sun
  5. Bo Li
  6. Jiapeng Hou
  7. Marian Difiglia
  8. James Palacino
  9. Zhi-Ying Wu
  10. Lixiang Ma
  11. Juan Botas
  12. Boxun Lu
(2015)
A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity
eLife 4:e05449.
https://doi.org/10.7554/eLife.05449
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  3. Download .RIS

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.

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Author details

  1. Yuwei Yao

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Xiaotian Cui

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  3. Ismael Al-Ramahi

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Xiaoli Sun

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  5. Bo Li

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  6. Jiapeng Hou

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  7. Marian Difiglia

    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. James Palacino

    Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Zhi-Ying Wu

    Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  10. Lixiang Ma

    Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.

  11. Juan Botas

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Boxun Lu

    State Key Laboratory of Genetic Engineering, Department of Biophysics, School of Life Sciences, Fudan University, Shanghai, China
    For correspondence
    luboxun@fudan.edu.cn
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Mani Ramaswami, Trinity College Dublin, Ireland

Ethics

Animal experimentation: The mouse experiments were carried out following the general guidelines published by the Association for Assessment and Accreditation of Laboratory Animal Care. The Animal Care and Use Committee of the School of Medicine at Fudan University approved the protocol used in animal experiments (Approval #20140904).

Human subjects: The study involves obtaining dermal fibroblasts from human patients. The study was approved by the ethic community of IBS at Fudan University (No.28), strictly following their general guidelines for experiments involving human subjects. Verbal and written informed consent, and the consent to publish, were obtained from all patients.

Version history

  1. Received: November 7, 2014
  2. Accepted: March 2, 2015
  3. Accepted Manuscript published: March 4, 2015 (version 1)
  4. Version of Record published: March 25, 2015 (version 2)

Copyright

© 2015, Yao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yuwei Yao
  2. Xiaotian Cui
  3. Ismael Al-Ramahi
  4. Xiaoli Sun
  5. Bo Li
  6. Jiapeng Hou
  7. Marian Difiglia
  8. James Palacino
  9. Zhi-Ying Wu
  10. Lixiang Ma
  11. Juan Botas
  12. Boxun Lu
(2015)
A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity
eLife 4:e05449.
https://doi.org/10.7554/eLife.05449

Share this article

https://doi.org/10.7554/eLife.05449

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