Autism spectrum disorder (ASD) is among the most commonly inherited mental disorders, and it is thought that it has a complex genetic basis. However, there are several disorders caused by single-gene mutations that are associated with autism. These include fragile X syndrome (FXS) and tuberous sclerosis complex (TSC). Both FXS and TSC are caused by the lack of proteins that negatively regulate protein synthesis, and both disorders have been shown to have increases in protein synthesis. Mutations in another gene called phosphatase and tensin homolog (PTEN) have been linked to ASD. Mutations in the PTEN gene result in the loss of another protein that negatively regulates protein synthesis. Thus, certain types of ASD appear to be associated with increases in brain protein synthesis.
A more direct link between ASD and protein synthesis was reported recently. It was shown that a boy with classic autism had a chromosome translocation that was mapped to the EIF4E gene. This gene encodes a protein called eIF4E, which is intimately involved in regulating protein synthesis. Mutation screening identified two further unrelated autism families that harbored the same mutation in the EIF4E gene. Using molecular biological techniques, it was shown that this mutation should increase expression of the EIF4E gene, which in turn should increase the expression of the eIF4E protein. An increase in the expression of the eIF4E protein should therefore increase protein synthesis.
We hypothesize that increased protein synthesis in the brain can cause ASD. We have begun studying mice that overexpress eIF4E and will determine whether they exhibit behaviors that are consistent with ASD. We then will determine whether ASD-like behaviors exhibited by these mice are reversed by novel, small molecule inhibitors of protein synthesis. Finally, we will determine whether the eIF4E overexpressing mice have cellular and molecular abnormalities that are reversed by the small molecule protein synthesis inhibitors.
Mutations in genes that encode proteins that negatively regulate protein synthesis clearly are one cluster of genes associated with ASD, but it has yet to be directly demonstrated that increased protein synthesis in the brain causes ASD. Our studies will investigate whether mice that overexpress eIF4E exhibit ASD-like behaviors. Moreover, because point mutations in the EIF4E gene have been linked to autistic patients and families, these studies have direct relevance to ASD in humans. Thus, these studies will provide information concerning whether overexpression of eIF4E is a biological risk factor for ASD. Our studies should provide important information concerning the role of improperly regulated protein synthesis in ASD and could link ASD mechanistically at the level protein synthesis to FXS, TSC, and autistic patients with PTEN and EIF4E mutations. Moreover, the results of these studies would provide information for the design and use of compounds to therapeutically target eIF4E for treating patients with ASD.