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Interactome: new protein network maps the dense connections of autism

By Janet Fang | June 10, 2011, 1:36 PM PDT

By shifting the focus from genes to the proteins they produce, researchers have identified a densely connected network that may help reveal how autism develops.
The finding may lay down framework for developing new treatments, even for very different types of the disorder.
Classic autism is described by 3 cardinal characteristics: loss of language and communication, impaired social behavior, and repetitive movements. In related or syndromic autism disorders, these characteristics are part of a much larger set of symptoms.
Researchers have difficulties pinpointing the genetic basis of classic autism. Syndromic autism, which is often traced back to a gene, have 26 genes known to be associated with it.
Studying each of those singly and devising a therapy would take a lifetime, says study researcher Huda Zoghbi at Baylor College of Medicine.
“We had these 26 genes that seemed to have little to do with each other but still resulted in autism-like symptoms,” Zoghbi says. “We thought that perhaps they cause autism by interacting with some shared partners that function in pathways that lead to similar phenotypes” (or characteristics).
Proteins working together inside cells sometimes physically touch each other, ScienceNOW explains. Often, many of them will also link to a few central proteins that play a key role in a particular biological process.
To search for common molecular pathways that underpin autism, Zoghbi and colleagues mapped thousands of protein-protein interactions to create a network – or an interactome – that highlights tightly connected proteins.
With a library of DNA sequences – and using those 26 known autism-associated proteins as bait – the team ‘caught’ 539 proteins that form connections in the brains of autism patients.
In other words, all of the proteins that are linked to autism individually are all connected to each other in some way by sharing partner proteins.
Pictured here is a portion of the network showing how proteins encoded by autism-associated genes (red circles) share many partner proteins (yellow). The turquoise lines are previously known interactions; the green lines are newly identified ones.

• Their map also shows that 2 proteins associated with classic autism – SHANK3 and TSC1, previously thought to be unrelated – interact with each other and share 21 protein partners.
• As it turns out, the molecular pathways in the brains of autistic individuals are closely related to genetic, nervous system conditions like Fragile X syndrome, Angelman syndrome, Rett syndrome, tuberous sclerosis, and Phelan-McDermid syndrome.

The interactome’s functional approach “can help us understand how mutations in different genes can cause similar clinical symptoms,” Zoghbi says.
The study was published in Science Translational Medicine this week.
Three other autism studies (here, here, and here) were published in Neuron this week, linking autism to hundreds of spontaneous genetic mutations. Nature News reports on some findings:

• Spontaneous duplications or deletions of at least 130 sites in the genome could contribute to the risk of autism.
• Deletion of a chromosome 7 region is associated with Williams–Beuren Syndrome, a condition linked to hypersocial behavior. Duplication of the same region is associated with autism, which is linked to antisocial behavior.
• Why are boys 4 times more likely to have autism than girls? Turns out, girls with autism tend to have many more mutated genes than boys with the disorder, suggesting that it generally takes a larger genomic change to cause autism in girls.

Overall, the results have lengthened, considerably, the list of genes that may have a role in causing autism. They’re nice early steps toward revealing pathways to help pin the condition down.
Image: Yasunari Sakai, Huda Zoghbi, Chad Shaw