Affiliation:
1. Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School
2. Graduate Program in Neuroscience, Rutgers University
3. Center for Advanced Biotechnology and Medicine, Rutgers University
4. Department of Genetics, Rutgers University
5. Department of Pediatrics, Rutgers Robert Wood Johnson Medical School
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.
Funder
New Jersey Governor's Council for Medical Research and Treatment of Autism
Nancy Lurie Marks Family Foundation
New Jersey Health Foundation
Mindworks Charitable Lead Trust
Jewish Community Foundation of Greater MetroWest NJ
Autism Science Foundation
Rutgers School of Graduate Studies
National Institutes of Health
Publisher
eLife Sciences Publications, Ltd
Cited by
1 articles.
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