Scientists Create Most Detailed Map Yet of Proteins Linked to Autism

Scientists have mapped a network of interacting proteins, to create a “blueprint” of some of the molecular changes that are associated with autism spectrum disorder. The new map is the largest of its kind and tracks over 1800 proteins that may play molecular roles in the condition. The results, published recently in the journal Science, are a “tour de force,” one that creates a “scalable approach” that can group together genes, based on shared biology, says Ryan Dhindsa, a genomics researcher at Baylor College of Medicine, who was not part of the study.

Autism spectrum disorder (ASD) is characterized by rigid and repetitive behaviors, communication differences, and sensory sensitivities. The developmental disability affects an estimated 1 out of every 31 people in the U.S., runs in families, and is highly heritable, suggesting a genetic component. However, the underlying biology is highly complex, with hundreds of variations in genes and the proteins they produce potentially involved in autism. Individuals with the highest level of need—those who have severe intellectual disability and very limited language—often have co-occurring conditions, such as epilepsy or motor delays, and tend to carry more genetic variants linked to autism.

For this study, Matthew State, a psychiatrist and genetics researcher at the University of California San Francisco, and his collaborators looked at 100 gene variants common in these severe autism cases. These selected variants change the structure of the proteins they produce. Nevan Krogan, a molecular biologist at the University of California San Francisco, and his collaborators introduced 100 of these autism-associated proteins into cells, then “pulled” them out again, to identify which other proteins came along for the ride. Over 1,800 additional proteins emerged, and the team mapped them based on their known function and predicted interactions with other proteins.

To learn more about some of these protein intersections and what they might mean for the brain, the team used an artificial intelligence platform called Alpha Fold to select different protein variants to test in lab-grown brain organoids. One of these proteins, called FOXP1, is involved in brain development. Krogan and his colleagues found that when FOXP1 wasn’t working properly, this led to another protein, called FOXP4, to go “rogue,” working in different ways than it usually does. Krogan and his collaborators were also able to identify the interactions of another group of proteins, called DCAF7, DYRK1A and KIAA0232. Researchers knew that this group formed a protein complex and affected brain development, but the new study revealed exactly how the individual protein structures fit together.

“Autism may have hundreds of different genetic starting points, but this study suggests that many of those different roads converge on the same molecular intersections,” says Christian Schaaf, a genetics researcher at the University of Heidelberg, who was not involved in the work. Such a map could help researchers learn more about what is driving autism and lead to treatment options for the most severe cases. Krogan notes that the method that the team used to build their map could also be used to study other conditions which have a strong genetic component, such as schizophrenia or obsessive-compulsive disorder.