The critical role of membralin in postnatal motor neuron survival and disease

  1. Bo Yang
  2. Mingliang Qu
  3. Rengang Wang
  4. Jon E Chatterton
  5. Xiao-Bo Liu
  6. Bing Zhu
  7. Sonoko Narisawa
  8. Jose Luis Millan
  9. Nobuki Nakanishi
  10. Kathryn Swoboda
  11. Stuart A Lipton
  12. Dongxian Zhang  Is a corresponding author
  1. Eugenom, Inc., United States
  2. Shanghai Yuanqi Clinical Lab Ltd., China
  3. Sanford-Burnham Medical Research Institute, United States
  4. University of California, Davis, United States
  5. Massachusetts General Hospital, United States

Abstract

Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, are predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induce ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

Article and author information

Author details

  1. Bo Yang

    Eugenom, Inc., San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mingliang Qu

    Shanghai Yuanqi Clinical Lab Ltd., Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Rengang Wang

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jon E Chatterton

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiao-Bo Liu

    Electron Microscopy Laboratory, Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Bing Zhu

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sonoko Narisawa

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jose Luis Millan

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nobuki Nakanishi

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kathryn Swoboda

    Department of Neurology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Stuart A Lipton

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Dongxian Zhang

    Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, La Jolla, United States
    For correspondence
    dzhang@sbmri.org
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All described procedures for animal were approved by the Institutional Animal Care and Use Committee of Sanford-Burnham Medical Research Institute and conducted in compliance with the Guide for the Care and Use of Laboratory Animals (Animal Use Form #14-060). Both sexes of mice were used for experiments and maintained in an institute facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Reviewing Editor

  1. Freda Miller, The Hospital for Sick Children Research Institute, University of Toronto, Canada

Publication history

  1. Received: January 15, 2015
  2. Accepted: May 15, 2015
  3. Accepted Manuscript published: May 15, 2015 (version 1)
  4. Version of Record published: June 10, 2015 (version 2)

Copyright

© 2015, Yang 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. Bo Yang
  2. Mingliang Qu
  3. Rengang Wang
  4. Jon E Chatterton
  5. Xiao-Bo Liu
  6. Bing Zhu
  7. Sonoko Narisawa
  8. Jose Luis Millan
  9. Nobuki Nakanishi
  10. Kathryn Swoboda
  11. Stuart A Lipton
  12. Dongxian Zhang
(2015)
The critical role of membralin in postnatal motor neuron survival and disease
eLife 4:e06500.
https://doi.org/10.7554/eLife.06500
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