1. Neuroscience
  2. Stem Cells and Regenerative Medicine
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Stem cell-derived cranial and spinal motor neurons reveal proteostatic differences between ALS resistant and sensitive motor neurons

  1. Disi An
  2. Ryosuke Fujiki
  3. Dylan E Iannitelli
  4. John W Smerdon
  5. Shuvadeep Maity
  6. Matthew F Rose
  7. Alon Gelber
  8. Elizabeth K Wanaselja
  9. Ilona Yagudayeva
  10. Joun Y Lee
  11. Christine Vogel
  12. Hynek Wichterle
  13. Elizabeth C Engle
  14. Esteban Orlando Mazzoni  Is a corresponding author
  1. New York University, United States
  2. Boston Children's Hospital, United States
  3. Columbia University Medical Center, United States
  4. Boston Childrens Hospital, United States
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Cite this article as: eLife 2019;8:e44423 doi: 10.7554/eLife.44423

Abstract

In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.

Article and author information

Author details

  1. Disi An

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ryosuke Fujiki

    Department of Neurology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Dylan E Iannitelli

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7654-9433
  4. John W Smerdon

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shuvadeep Maity

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6031-4744
  6. Matthew F Rose

    Department of Neurology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1148-4130
  7. Alon Gelber

    Department of Neurology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Elizabeth K Wanaselja

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ilona Yagudayeva

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joun Y Lee

    Department of Neurology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Christine Vogel

    Department of Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2856-3118
  12. Hynek Wichterle

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7817-0080
  13. Elizabeth C Engle

    Department of Neurology, Boston Childrens Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Esteban Orlando Mazzoni

    Department of Biology, New York University, New York, United States
    For correspondence
    eom204@nyu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8994-681X

Funding

PROJECT ALS (A13-0416)

  • Esteban Orlando Mazzoni

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD079682)

  • Esteban Orlando Mazzoni

NYDH (DOH01-C32243GG-3450000)

  • Esteban Orlando Mazzoni

MODBDF (#5-FY14-99)

  • Esteban Orlando Mazzoni

National Institute of Neurological Disorders and Stroke (F31 NS 095571)

  • John W Smerdon

National Institute of Neurological Disorders and Stroke (F31 103447)

  • Dylan E Iannitelli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Protocols were approved by Columbia University and Harvard University

Reviewing Editor

  1. Paola Arlotta, Harvard University, United States

Publication history

  1. Received: December 15, 2018
  2. Accepted: June 2, 2019
  3. Accepted Manuscript published: June 3, 2019 (version 1)

Copyright

© 2019, An 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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