Protein synthesis at synapses in the pathogenesis and therapy of autism
Ray Kelleher, M.D., Ph.D.
Massachusetts General Hospital
New protein synthesis is essential for long-lasting memory, and regulation of neuronal translation by the ERK and mTOR signaling pathways plays 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 at Massachusetts General Hospital and his colleague Mark Bear at the Massachusetts Institute of Technology to propose that ‘troubled translation’ may be a core pathophysiological mechanism in autism. Kelleher, Bear and their teams investigated this hypothesis using a multidisciplinary approach that combined the generation of novel mouse models with biochemical, electrophysiological and behavioral analysis.
Through comparative analysis of mouse models of fragile X and TSC, the researchers found that genetic defects in these disorders perturb neuronal protein synthesis in different ways. Their investigations have also helped to pinpoint how translational dysregulation produces autism-related phenotypes in these disorders. Their findings suggest that altered neuronal protein synthesis — either too much or too little — is a convergent mechanism underlying some forms of autism, as well as a potential target for development of novel treatments.