Researchers at the Hebrew University of Jerusalem report that increased nitric oxide signaling can chemically modify the protein TSC2, reducing its levels and allowing the mTOR pathway to become overactive—a chain of events they say appears in laboratory models and in samples from some children diagnosed with autism spectrum disorder.
A study from the Hebrew University of Jerusalem reports evidence that nitric oxide—a small signaling molecule that helps regulate brain-cell communication—may, in some situations, set off a molecular cascade tied to autism spectrum disorder (ASD).
According to the researchers, elevated nitric oxide activity can drive S-nitrosylation, a chemical modification that alters the behavior of proteins. In their experiments, nitric oxide-mediated S-nitrosylation affected TSC2, a protein that normally serves as a brake on the mTOR pathway, a central regulator of cellular growth and protein production. The study reports that when TSC2 is modified in this way, it becomes marked for removal, lowering TSC2 levels and allowing mTOR signaling to rise.
The work was led by Prof. Haitham Amal, The Satell Family Professor of Brain Sciences, and first-authored by PhD student Shashank Ojha. The findings were published in Molecular Psychiatry, the university said.
To test whether the pathway could be interrupted, the team used pharmacological methods to reduce nitric oxide production in neurons. The researchers report that lowering nitric oxide prevented the TSC2 modification and brought mTOR activity back toward typical levels in their experimental system. In a separate approach, they engineered a modified version of TSC2 designed to resist nitric oxide-related modification; the study reports that this also helped preserve TSC2 levels and reduced downstream effects associated with excessive mTOR signaling.
The researchers also analyzed clinical samples from children diagnosed with ASD, including children with SHANK3 mutations and children with idiopathic ASD (cases without a single known genetic cause). Participants were recruited by Dr. Adi Aran, MD, the release said. In these samples, the team reported reduced TSC2 levels and increased activity in the mTOR signaling pathway, consistent with the laboratory findings.
“Autism is not one condition with one cause, and we don’t expect one pathway to explain every case,” Amal said in a statement. “But by identifying a clearer chain of events, how nitric oxide-related changes can affect a key regulator like TSC2 and, in turn, mTOR, we hope to provide a more precise map for future research and, eventually, more targeted therapeutic ideas.”
The authors framed the findings as a potential roadmap for investigating signaling imbalances in ASD and suggested nitric oxide inhibitors as possible tools for future research. The researchers also emphasized that ASD is highly heterogeneous and is associated with differences in social communication and behavior, with risk influenced by a range of genetic and biological factors.
