UCSF Scientists Map Over 1,800 Protein Interactions Tied to Profound Autism, Opening Path to Drug Targets

Scientists at UC San Francisco have produced what they describe as a molecular atlas of protein interactions linked to profound autism — a form of the condition characterized by severe intellectual disability, limited verbal ability, and frequent co-occurring conditions such as epilepsy. The study, published in the journal Science, maps more than 1,800 interactions among proteins that originate from hundreds of high-risk autism genes.

The work was led by Nevan Krogan, director of the UCSF Quantitative Biosciences Institute, and Dr. Matthew State, a clinical psychiatrist and geneticist at UCSF. The two researchers, introduced by a mutual colleague more than a decade ago, combined complementary expertise: State's work identifying high-risk autism genes and Krogan's technologies for probing protein interactions. "What we've been missing is the mechanistic understanding of how these mutations are seemingly resulting in autism," Krogan said. "In order to understand that, you need to go to the proteins."

The team selected 100 proteins from high-risk autism genes, injected them into lab-grown cells, and retrieved them along with any proteins that attached. They then used AlphaFold to identify which proteins were in direct contact. "Where AI is playing an important role is being predictive about who's talking to who," Krogan said, noting that determinations that once took years can now be made in roughly an hour. Researchers also introduced patient-specific mutations to observe how protein interactions changed — in one case, a weakened connection between two proteins caused a third to activate genes associated with neurodevelopmental defects in organoids.