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Control of synaptic protein synthesis in the pathogenesis and therapy of autism

Ray Kelleher, M.D., Ph.D.
Massachusetts General Hospital

As the number of genes linked to autism spectrum disorders steadily increases, it becomes important for researchers to identify how the gene products affect brain cells, leading to features of autism. Several studies have suggested that dysfunction at synapses, the connections between brain cells, may be a common theme in autism pathogenesis, but a better understanding of the underlying mechanisms is crucial in the effort to translate these genetic discoveries into therapies.

The synthesis of new proteins near synapses is essential for long-lasting learning and memory. The synaptic changes that are thought to underlie processes such as learning and memory are referred to as ‘synaptic plasticity’. Ray Kelleher and his colleagues at the Massachusetts General Hospital have been investigating how synaptic proteins are synthesized, and how altered regulation of this process can perturb brain structure and function, particularly synaptic plasticity and cognitive function.

Interestingly, the gene products responsible for several disorders with high prevalence among those on the autism spectrum, such as fragile X syndrome and tuberous sclerosis complex, cluster in pathways that regulate protein synthesis. Based on these and other observations, Kelleher and Mark Bear of the Massachusetts Institute of Technology propose that loss of the normal controls on synaptic protein synthesis may be a common pathogenic mechanism leading to the development of autism-related phenotypes.

The researchers plan to evaluate this hypothesis by performing a comparative, multidisciplinary analysis of mouse models of fragile X and tuberous sclerosis, focusing on protein synthesis as it relates to autism. These experiments will take advantage of new mouse models that target autism-linked mutations specific to subsets of neurons at certain developmental stages. The researchers also plan to investigate whether genetic and pharmacologic modulation of synaptic protein synthesis can correct autism-related phenotypes in these mouse models. The researchers hope that their results will advance understanding of shared pathogenic mechanisms in autism and open the way to novel therapeutic strategies.