2024-03-27 ラトガース大学
<関連情報>
- https://www.rutgers.edu/news/study-different-autism-types-finds-shared-mechanism-may-respond-drugs
- https://elifesciences.org/articles/82809
特発性および16p11.2欠失自閉症の神経前駆細胞において、mTORシグナル伝達の調節不全が共通の神経突起および遊走障害を媒介することが明らかになった。 Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells
Smrithi Prem ,Bharati Dev,Cynthia Peng,Monal Mehta,Rohan Alibutud,Robert J Connacher,Madeline St Thomas,Xiaofeng Zhou,Paul Matteson,Emanuel DiCicco-Bloom
eLife Published:Mar 25, 2024
DOI:https://doi.org/10.7554/eLife.82809
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.
