Autism spectrum disorder has long been associated with irregular signaling in the mTOR pathway, a cellular system that governs protein production and cell growth — but the upstream trigger for that irregularity has remained poorly understood. Researchers at The Hebrew University of Jerusalem now say they have identified a molecular sequence that connects a common brain chemical to that dysfunction.
The study, published in Molecular Psychiatry and led by Prof. Haitham Amal, The Satell Family Professor of Brain Sciences, with PhD student Shashank Ojha as first author, centers on nitric oxide — a small signaling molecule that normally helps fine-tune communication between neurons. According to the announcement, in certain forms of autism spectrum disorder (ASD), rising nitric oxide levels appear to set off a biochemical chain reaction rather than performing their usual regulatory function.
The Molecular Sequence
The mechanism the team identified involves a process called S-nitrosylation, in which nitric oxide attaches directly to proteins and changes how they behave. Using a systems-level protein analysis, the researchers found that multiple proteins connected to the mTOR pathway were affected by this modification. That finding led them to focus specifically on TSC2, a protective protein that normally functions as a brake on mTOR activity.
The experiments showed that nitric oxide can modify TSC2 in a way that marks it for removal from the cell. As TSC2 levels fall, its braking effect on mTOR weakens. The pathway then becomes overactive, interfering with how neurons produce proteins and communicate — cellular effects the study associates with ASD-related biology.
The logic of the cascade, as the researchers describe it, is sequential: elevated nitric oxide triggers S-nitrosylation of TSC2, TSC2 degrades, and mTOR signaling surges beyond normal levels. Each step depends on the one before it, which is precisely what made the pathway testable as an intervention point.
Blocking the Cascade
To determine whether the chain reaction could be interrupted, the team used pharmacological methods to reduce nitric oxide production in neurons. The report states that when nitric oxide signaling was lowered, the S-nitrosylation of TSC2 did not occur. As a consequence, mTOR activity returned to normal levels, and the researchers observed improvements in measurements linked to altered protein translation and autism-related cellular effects in their experimental system.
A complementary approach involved engineering modifications at the molecular level to further confirm the pathway’s directionality — that TSC2 degradation was a downstream consequence of nitric oxide activity rather than an independent event.
The study does not claim a universal explanation for ASD, which encompasses a wide range of presentations and genetic backgrounds. What it offers, according to the researchers, is a defined biological pathway — from a known signaling molecule to a known regulatory protein to a known cellular system — that connects environmental and molecular risk factors to brain-level changes observed in some forms of the condition. The identification of a specific, interruptible step in that sequence gives researchers a concrete target for further investigation into both the biology of ASD and potential therapeutic approaches.
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