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
Research Article
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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.

Data availability

Sequencing data have been deposited in GEO under accession code GSE130938.

The following data sets were generated

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)
  4. Version of Record published: June 26, 2019 (version 2)

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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Further reading

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    Population receptive field (pRF) modeling is a popular fMRI method to map the retinotopic organization of the human brain. While fMRI-based pRF maps are qualitatively similar to invasively recorded single-cell receptive fields in animals, it remains unclear what neuronal signal they represent. We addressed this question in awake nonhuman primates comparing whole-brain fMRI and large-scale neurophysiological recordings in areas V1 and V4 of the visual cortex. We examined the fits of several pRF models based on the fMRI blood-oxygen-level-dependent (BOLD) signal, multi-unit spiking activity (MUA), and local field potential (LFP) power in different frequency bands. We found that pRFs derived from BOLD-fMRI were most similar to MUA-pRFs in V1 and V4, while pRFs based on LFP gamma power also gave a good approximation. fMRI-based pRFs thus reliably reflect neuronal receptive field properties in the primate brain. In addition to our results in V1 and V4, the whole-brain fMRI measurements revealed retinotopic tuning in many other cortical and subcortical areas with a consistent increase in pRF size with increasing eccentricity, as well as a retinotopically specific deactivation of default mode network nodes similar to previous observations in humans.

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    The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes.