Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Graduate Program in Neuroscience, Rutgers University, Piscataway, United States
Bharati Dev
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States
Cynthia Peng
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States
Monal Mehta
Graduate Program in Neuroscience, Rutgers University, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United States
Rohan Alibutud
Department of Genetics, Rutgers University, Piscataway, United States
Robert J Connacher
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Graduate Program in Neuroscience, Rutgers University, Piscataway, United States
Madeline St Thomas
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Graduate Program in Neuroscience, Rutgers University, Piscataway, United States
Xiaofeng Zhou
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States
Paul Matteson
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United States
Department of Genetics, Rutgers University, Piscataway, United States
James H Millonig
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, United States
Department of Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States; Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, United States
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.