New protein synthesis is essential for long-lasting memory, and the proteins ERK and mTOR, which regulate gene translation, have a crucial role in this process. Several monogenic syndromes associated with autism, notably fragile X syndrome and tuberous sclerosis complex (TSC), involve proteins that function in these translational regulatory pathways.
These observations led Ray Kelleher and his colleagues at Massachusetts General Hospital, in collaboration with Mark Bear at the Massachusetts Institute of Technology, to the hypothesis that ‘troubled translation’ may be a core pathophysiological mechanism in autism. Kelleher has investigated this hypothesis using a multidisciplinary approach that combines the generation of novel mouse models with biochemical, electrophysiological and behavioral analysis of the mice.
Through comparative analysis of mouse models of fragile X and TSC, including mice in which genetic manipulations are targeted to specific neuronal subpopulations, Kelleher and Bear aim to understand how dysregulation of neuronal protein synthesis produces autism-related phenotypes in these disorders.
They also plan to test whether genetic and pharmacological interventions can correct synaptic and behavioral deficits by normalizing the synthesis of specific proteins. These studies may provide insight into pathophysiological mechanisms, novel therapeutic targets and potential biomarkers in autism.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
