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 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. Hundreds of variations in genes and the proteins they produce may be involved in autism.

The new map is the largest of its kind and tracks over 1800 proteins that may play molecular roles in the condition.  “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.

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. Such a map could help researchers learn more about what is driving autism and lead to treatment options for the most severe cases.

Autism Is Very Diverse

Autism spectrum disorder (ASD) is characterized by rigid and repetitive behaviors, communication differences, and sensory sensitivities. The condition looks very different from person to person, with individuals showing a wide range of traits.

(This is how autism looks different in girls and women.)

Some autistic people can live fully independent lives, pursuing higher education, a career, and a family, while others may need a very high amount of support, including round-the-clock care. Many more people fall somewhere in-between.

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, which affect their coordination and ability to produce speech. They also tend to carry more genetic variants linked to autism.

“They are the highest need population,” says Matthew State, a psychiatrist and genetics researcher at the University of California San Francisco, and one of the authors of the paper. “That’s the focus of our thinking about therapeutics.”

Mapping Protein Interactions in Autism

For this study, State 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.

Proteins are the functional units that make up the complex machinery of the cell, says Nevan Krogan, a molecular biologist at the University of California San Francisco, and one of the authors of the paper. When parts of this machinery get altered, this changes how the machine works, in ways that can be very hard to predict, if you are just looking at one protein, or one set of proteins, rather than the entire machinery.

For this experiment, Krogan and his collaborators introduced 100 of these autism-associated proteins into cells, then “pulled” them out again, in order 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.

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.

(Scientists are starting to understand how autism and ADHD can overlap.)

Autism Genes Converge in Unexpected Ways

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. This is an example of how losing one gene can lead to a gain of new functions in another gene, Dhindsa says.

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—essentially a molecular machine within the cell—and affected brain development, but the new study revealed exactly how the individual protein structures fit together.

More broadly speaking, the 100 proteins the study began with serve diverse functions, such as directing which genes turn on or off or playing a role in the structural integrity of cells, and at face value, don’t have a lot in common. But the team found that there were many more intersections between these proteins than would be expected, and that many of these proteins intersect at common points. These are discoveries that can link together different groups of patients, that were previously thought to be separate, but who may respond to similar therapies, Krogan says.

The idea that, in autism, these proteins may interact in overlapping ways, a phenomenon known as convergence, has been proposed in the past, by a number of scientists in the field. This study has added considerable evidence to support this theory, by creating the largest, most detailed map to date. “This is really coloring in the picture considerably,” says Daniel Geschwind, a genetics researcher at the University of California Los Angeles, who was not involved in the study.

The Map Could Point to Potential Therapeutics

The results offer a more systemic understanding of the underlying biology of autism. In the past, autism was thought of as a condition that could be caused by dozens of unrelated factors, which would need dozens of different therapies to treat. As this map suggests, there is far more commonality than previously realized, which also means that potential therapies may work for many more people than expected. These overlap points are areas for scientists to dive deeper with future studies. “This is hypothesis generating” research, Dhindsa says.

The findings also open up the list of possible proteins, and protein complexes, that can be targeted, in order to develop new therapies. “One of the next revolutions in drug discovery is going to be looking at drug discovery through the lens of protein interactions and protein complexes,” Krogan says. “Looking at the protein interaction network really gives you multiple shots on goal.”

Ultimately, research like this can help us come up with ways to offer better, more individualized support for autistic people and their families, says Christina Collura, a teacher and autism advocate, who lives in Ontario, Canada.

What’s important, Collura says, is that these therapies offer support in a way that meets individuals, and their families, where they are. “Understanding the biology of autism should never mean losing sight of the person,” Collura says.