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
Share this article
Cite this article
  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
  2. Download BibTeX
  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.

Article and author information

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.

Metrics

  • 3,989
    views
  • 1,069
    downloads
  • 62
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Research organisms

Further reading

    1. Cell Biology
    2. Neuroscience

    Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier

    Mariana I Tsap, Andriy S Yatsenko ... Halyna R Shcherbata
    Research Article Updated

    Mutations in Drosophila Swiss cheese (SWS) gene or its vertebrate orthologue neuropathy target esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.

    1. Neuroscience

    Inferring control objectives in a virtual balancing task in humans and monkeys

    Mohsen Sadeghi, Reza Sharif Razavian ... Dagmar Sternad
    Research Article

    Natural behaviors have redundancy, which implies that humans and animals can achieve their goals with different strategies. Given only observations of behavior, is it possible to infer the control objective that the subject is employing? This challenge is particularly acute in animal behavior because we cannot ask or instruct the subject to use a particular strategy. This study presents a three-pronged approach to infer an animal’s control objective from behavior. First, both humans and monkeys performed a virtual balancing task for which different control strategies could be utilized. Under matched experimental conditions, corresponding behaviors were observed in humans and monkeys. Second, a generative model was developed that represented two main control objectives to achieve the task goal. Model simulations were used to identify aspects of behavior that could distinguish which control objective was being used. Third, these behavioral signatures allowed us to infer the control objective used by human subjects who had been instructed to use one control objective or the other. Based on this validation, we could then infer objectives from animal subjects. Being able to positively identify a subject’s control objective from observed behavior can provide a powerful tool to neurophysiologists as they seek the neural mechanisms of sensorimotor coordination.

    1. Neuroscience

    Retinal metabolism displays evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle

    Yiyi Chen, Laimdota Zizmare ... Christoph Trautwein
    Research Article

    The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilised 1H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: (1) the mini-Krebs-cycle, fuelled by glutamine and branched chain amino acids, generating N-acetylaspartate; (2) the alanine-generating Cahill-cycle; (3) the lactate-releasing Cori-cycle. Moreover, the metabolomics data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.