Defects in translational regulation contributing to human cognitive and behavioral disease

Abstract

Recent data suggest that the levels of many synaptic proteins may be tightly controlled by the opposing processes of new translation and protein turnover in neurons. Alterations in this balance or in the levels of such dosage-sensitive proteins that result in altered stoichiometry of protein complexes at developing and remodeling synapses may underlie several human cognitive diseases including Fragile X Syndrome, autism spectrum disorders, Angelman syndrome and non-syndromic mental retardation. While a significant amount is known about the transduction of membrane signals to the translational apparatus through kinase cascades acting on general translation factors, much less is understood about how such signals may influence the activity of mRNA-specific regulators, their mechanisms of action and the specific sets of mRNAs they regulate. New approaches to the unbiased in vivo identification of maps of binding sites for these proteins on mRNA is expected to greatly increase our understanding of this crucial level of regulation in neuronal development and function.