SAN FRANCISCO — Researchers at the University of California, San Francisco have created what they describe as the largest molecular interaction map of autism to date, identifying shared protein networks that could provide new targets for precision therapies.
The study, published in Science, mapped more than 1,800 protein-protein interactions across 100 high-confidence autism risk genes. Researchers said 87% of the interactions had not previously been reported.
The work was conducted by scientists at UCSF’s Quantitative Biosciences Institute and Department of Psychiatry and Behavioral Sciences following more than a decade of research into how autism-linked genetic mutations affect brain development.
Rather than examining autism-associated genes alone, the researchers studied the proteins encoded by those genes and how disease-causing mutations altered their interactions.
The analysis found that genetically different forms of autism often disrupted the same protein complexes, suggesting that therapies targeting common molecular pathways could potentially benefit patients with multiple genetic forms of the condition.
Researchers also analyzed 54 autism-associated mutations derived from patients to determine how individual genetic variants altered protein interaction networks.
“After the initial excitement of discovering rare mutations that cause common forms of autism, the reality of how hard it would be to develop medicines to target the most severe end of the autism spectrum became abundantly clear,” said Matthew W. State, M.D., Ph.D., senior author and Chair of the Department of Psychiatry and Behavioral Sciences at UCSF. “This current work opens up a whole new world of possibilities for therapeutic targets and promises a generation of novel drugs that can transform what we are able to do in the clinic.”
The researchers said the findings may be particularly relevant to people with profound autism associated with rare, high-impact mutations in established autism risk genes.
One focus of the study involved the FOXP1 and FOXP2 genes. Researchers found that separate autism-associated mutations in the genes could disrupt the same interaction between the FOXP1 and FOXP4 proteins.
Experiments using laboratory-grown brain organoids indicated that these disruptions were associated with premature development of cortical neurons and increased neural circuit excitability.
The team also combined the protein interaction data with AlphaFold structural predictions to determine where mutations interfere with protein interfaces. Researchers said the approach could help identify molecules capable of stabilizing beneficial protein interactions or blocking harmful ones.
The study also identified examples in which mutations appeared to produce harmful gains of function rather than simply causing a loss of normal protein activity.
In the case of FOXP1, mutations located in different areas of the protein were found to disrupt the same FOXP1-FOXP4 interaction and trigger abnormal activity involving FOXP4.
“The science demonstrates that autism is written in our genes,” said Nevan J. Krogan, Ph.D., Professor at UCSF, Director of QBI and senior investigator at Gladstone Institutes. “This study maps the exact molecular machinery that is altered, including the specific protein interactions, down to the interfaces we can target with a drug.”
Krogan said the research platform could also be applied to other diseases, including neurodegenerative conditions and cancer.
The researchers said the findings could provide an alternative therapeutic strategy to approaches that target individual genes, including antisense oligonucleotides and CRISPR-based therapies. Targeting shared protein pathways could potentially allow a single therapy to address several genetic forms of autism.
The study was led by co-first authors Belinda Wang, M.D., Ph.D., Rasika Vartak, Ph.D., and Kelsey Hennick, Ph.D., along with co-corresponding authors Kirsten Obernier, Ph.D., Tomasz J. Nowakowski, Ph.D., and A. Jeremy Willsey, Ph.D.
The work is part of the Psychiatric Cell Map Initiative, a collaboration between QBI and UCSF’s Department of Psychiatry and Behavioral Sciences focused on understanding the molecular mechanisms underlying neuropsychiatric disorders.
QBI previously used a similar protein-interaction mapping approach during the COVID-19 pandemic to identify potential drug candidates targeting interactions between SARS-CoV-2 and human proteins.
Researchers said the autism study establishes a broader framework for connecting genetic mutations with protein networks, disease mechanisms and potential therapeutic targets that could be applied across multiple areas of medicine.
