Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells

Abstract

Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.

Data availability

Genome Wide Sequencing data has been deposited into the NIH NDA. All excel sheets for graphs in the manuscript as well as unedited western blot films (labeled and unlabeled) will be deposited in Dryad: DOI: 10.5061/dryad.6wwpzgn5v

The following data sets were generated

Article and author information

Author details

  1. Smrithi Prem

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    For correspondence
    prems@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6961-7904
  2. Bharati Dev

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cynthia Peng

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Monal Mehta

    Graduate Program in Neuroscience, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rohan Alibutud

    Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Robert J Connacher

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Madeline St Thomas

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Xiaofeng Zhou

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Paul Matteson

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jinchuan Xing

    Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6469-8733
  11. James H Millonig

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    For correspondence
    millonig@cabm.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
  12. Emanuel DiCicco-Bloom

    Department of Neuroscience and Cell Biology, Rutgers, The State University of New Jersey, Piscataway, United States
    For correspondence
    diccem@rwjms.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5091-1046

Funding

NIH R25 (5R25MH119043-05)

  • Smrithi Prem

Rutgers School of Graduate Studies (Thesis Finishing Grant)

  • Smrithi Prem

New Jersey Governer's Council For Medical Resear (CAUT13APS010,CAUT14APL031,CAUT15APL041,CAUT19APL014)

  • James H Millonig
  • Emanuel DiCicco-Bloom

Nancy Lurie Marks Family Foundation

  • James H Millonig
  • Emanuel DiCicco-Bloom

NJ Health Foundation (PC 63-19)

  • James H Millonig

Mindworks Charitable Lead Trust

  • Emanuel DiCicco-Bloom

Jewish Community Foundation o Greater MetroWest

  • Emanuel DiCicco-Bloom

Autism Science Foundation (Summer Undergraduate Research Grant)

  • Cynthia Peng

New Jersey Governor's Council for Medical Research and Treatment of Autism (CAUT19APL028)

  • Smrithi Prem
  • Jinchuan Xing
  • Emanuel DiCicco-Bloom

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

Copyright

© 2024, Prem 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. Smrithi Prem
  2. Bharati Dev
  3. Cynthia Peng
  4. Monal Mehta
  5. Rohan Alibutud
  6. Robert J Connacher
  7. Madeline St Thomas
  8. Xiaofeng Zhou
  9. Paul Matteson
  10. Jinchuan Xing
  11. James H Millonig
  12. Emanuel DiCicco-Bloom
(2024)
Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells
eLife 13:e82809.
https://doi.org/10.7554/eLife.82809

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https://doi.org/10.7554/eLife.82809