Dysregulation of the integrated stress response pathway in fragile X syndrome

  • Awarded: 2019
  • Award Type: Pilot
  • Award #: 611773

Several brain disorders, with high rates of autism, such as tuberous sclerosis, PTEN hamartoma syndrome and fragile X syndrome (FXS), are associated with a loss of function of translational repressors, suggesting that the upregulation of protein synthesis might be an underlying mechanism in these conditions. This notion is further supported by studies in animal models of autism showing that deviations from the optimal level of synaptic protein synthesis lead to an impairment in neuronal circuitry and contribute to the development of autism traits.

The Fmr1 knockout (KO) mouse model recapitulates many phenotypes observed in individuals with FXS, including impairments in social interaction and repetitive behaviors. Fmr1 KO mice also display increased global mRNA translation, which is thought to strongly contribute to the pathophysiology observed in this mouse model.

The integrated stress response (ISR) pathway is regulated via phosphorylation of the alpha subunit of eIF2 (eIF2α) and controls translation initiation within cells. Arkady Khoutorsky and his colleagues at McGill University propose that dysregulation of the ISR pathway might contribute to increased general translation and abnormal synaptic and behavioral phenotypes in Fmr1 KO mice. In support of this hypothesis, Khoutorsky and colleagues have preliminary evidence that eIF2α phosphorylation (p-eIF2α) is altered in the cortex of Fmr1 KO mice and that normalization of p-eIF2α levels in the brain of Fmr1 KO mice can rescue some of the core behavioral phenotypes in these animals.

Khoutorsky now proposes to study the cell-type-specific activity of the ISR pathway along with other key signaling cascades that regulate protein synthesis (e.g., mTOR and ERK pathways). His group will also investigate the contribution that dysregulation of the ISR pathway plays in the aberrant activity of neuronal circuits and behavioral phenotypes in Fmr1 KO mice.

This work will provide a framework for analyzing all three major translational control signaling pathways (eIF2α, mTOR and ERK) as potential mediators of dysregulated translation in ASD and will help elucidate how different aspects of ASD pathophysiology could be engendered by alterations in different translational control mechanisms within diverse cell types.

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