Exaggerated Cap-Dependent Translation as a Mechanism for Corticostriatal Dysfunction in Fragile X Syndrome Model Mice
Abstract
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 altered protein synthesis. Mutations in another gene called phosphatase and tensin homolog (PTEN) have been linked to ASD. Mutations in the PTEN gene results in the loss of another protein that negatively regulates protein synthesis. Finally, two more direct links between ASD and protein synthesis have been reported. 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. Furthermore, it was shown that genetic variations in CYFIP1, encoding cytoplasmic FMRP interacting protein 1, are linked to ASD. Of note, CYFIP1 has two functions, one of them being a translational repressor. Thus, certain types of ASD appear to be associated with increases in brain protein synthesis. We previously showed that mice that overexpress eIF4E have increased brain protein synthesis that causes ASD-associated behaviors, including repetitive and perseverative behaviors. In addition, we have found that FXS model mice have increased eIF4E-mediated protein synthesis. Thus, we hypothesize that increased eIF4E-mediated protein synthesis in the brain contributes to altered neuronal communication and ASD-related behaviors exhibited by FXS model mice. Moreover, we hypothesize that the ASD-related behaviors displayed by the FXS model mice can be reversed by novel, small molecule inhibitors of eIF4E-mediated protein synthesis. Mutations in genes that encode proteins that negatively regulate protein synthesis clearly are one cluster of genes associated with ASD. Our studies will investigate whether ASD-like behaviors displayed by FXS model mice, which have been shown to exhibit increased eIF4E-mediated protein synthesis and ASD-like behaviors, can be returned to normal by inhibiting eIF4E. Thus, these studies will provide information concerning whether increased eIF4E-mediated protein synthesis is a biological risk factor for FXS and other types of ASD. Our studies should provide important information concerning the role of improperly regulated protein synthesis in FXS and could link FXS mechanistically at the level of eIF4E-meidated protein synthesis to 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 FXS and ASD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510360
Entities
People
- Eric Klann
Organizations
- New York University
- United States Army