Exploring the integrated stress response as a driver of autism features

  • Awarded: 2020
  • Award Type: Pilot
  • Award #: 722987

The integrated stress response (ISR) has recently emerged as a main causative driver of normal aging as well as a wide spectrum of cognitive disorders of vastly different etiologies, including Alzheimer’s and vanishing white matter disease, traumatic brain injury (TBI) and Down syndrome.

Peter Walter’s laboratory recently discovered a small-molecule ISR inhibitor, ISRIB, that reverses age-related memory decline in mice1 and alleviates cognitive deficits in several mouse models of cognitive dysfunction, remarkably without displaying overt toxicity. Intriguingly, in preliminary results, they found that ISRIB also alleviates social deficits observed after TBI. Social challenges are one of the core common features of autism spectrum disorder (ASD), and, indeed, ISR activation is prevalent in the brains of some ASD individuals and in several mouse models of ASD.

Walter and his team hypothesize that multiple risk factors for ASD converge on ISR induction, resulting in behavioral abnormalities. To test this hypothesis, they aim to perform preclinical studies to explore whether treatment with ISRIB could be of therapeutic value. They plan to determine whether different genetic ASD models (eg. Shank3b-/-, forebrain-specific Pten-/-, and forebrain-specific Tsc-/-) share common mechanistic translational features reminiscent of increased ISR and test the effect of ISRIB on three core criteria associated with ASD: social behavior deficits, repetitive behaviors and communication problems. Given ISRIB’s success in alleviating cognitive dysfunctions of vastly different molecular origins, there is hope that ISR inhibition may emerge as an effective ASD therapy.


1.Krukowski K. et al. Elife 9, e62048 (2020) PubMed
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