Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells
- Rutgers, The State University of New Jersey, United States
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
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Source Data for Dysregulation of mTOR Signaling Mediates Common Neurite and Migration Defects in Both Idiopathic and 16p11.2 Deletion Autism Neural Precursor CellsDryad Digital Repository, doi:10.5061/dryad.6wwpzgn5v.
Article and author information
Author details
Emanuel DiCicco-Bloom
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.
Reviewing Editor
- Genevieve Konopka, University of Texas Southwestern Medical Center, United States
Version history
- Received: August 18, 2022
- Preprint posted: September 20, 2022 (view preprint)
- Accepted: March 4, 2024
- Accepted Manuscript published: March 25, 2024 (version 1)
- Version of Record published: April 9, 2024 (version 2)
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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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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