Research ArticleNeuropsychiatry

Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders

Science Translational Medicine  08 Jun 2011:
Vol. 3, Issue 86, pp. 86ra49
DOI: 10.1126/scitranslmed.3002166

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Building Connections in Autism

Autism is a collection of neurodevelopmental disorders characterized by impaired social skills, delayed language development, and repetitive behaviors. In classic (idiopathic) autism, these three characteristics predominate, whereas in syndromic autism disorders, these characteristics are part of a much larger set of symptoms. Clearly, common molecular pathways should underlie these similar disorders but trying to identify these pathways has proved difficult. Genetic studies have implicated genes mutated in syndromic autism disorders such as fragile X syndrome, Angelman syndrome, and Rett syndrome. Meanwhile, recent genome-wide association studies have pinpointed a large number of susceptibility loci that may contribute to autism spectrum disorders. Now, Zoghbi and her team turn their attention from genes associated with autism to the proteins they encode. These authors have compiled a network of protein-protein interactions based on autism-associated genes with the aim of finding common molecular pathways that underpin both classic and syndromic autism.

The authors divided autism-associated genes into three groups and then used a yeast two-hybrid screen of a human complementary DNA library to obtain interacting partners for the products of 26 autism-associated genes. They then built a protein-protein interaction network and from it pulled out very highly connected proteins such as those known to be mutated in fragile X syndrome. Their network showed that two proteins, SHANK3 and PSD95, located in the postsynaptic region of neurons and known to be associated with classic autism interact with each other and share nine common protein binding partners. SHANK3 also interacts with the TSC1 protein mutated in a form of syndromic autism called tuberous sclerosis complex, and these two proteins share 21 binding partners. SHANK3 and TSC1 also associate with two other postsynaptic proteins, ACTN1 and HOMER3. With their protein interaction network as a guide, the authors then performed microarray-based comparative genome hybridization for genes encoding 627 proteins in the network using DNA from 288 patients with classic autism. They discovered four new gene mutations including a mutation in the FLNA gene encoding a protein that turns out to bind to SHANK3. This new protein-protein interaction network provides a starting point for elucidating the common molecular pathways that may underlie both classic and syndromic autism. It also provides a framework on which to build a much bigger autism interactome that could be used to develop drugs with potential for treating several different forms of autism.

Footnotes

  • Citation: Y. Sakai, C. A. Shaw, B. C. Dawson, D. V. Dugas, Z. Al-Mohtaseb, D. E. Hill, H. Y. Zoghbi, Protein Interactome Reveals Converging Molecular Pathways Among Autism Disorders. Sci. Transl. Med. 3, 86ra49 (2011).