Investigating the mechanisms of FMRP dysregulation due to the loss of TSC2

  • Awarded: 2018
  • Award Type: Explorer
  • Award #: 597631

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but the underlying molecular pathogenesis has remained poorly understood. There are several syndromes that are known to be highly associated with the development of ASD, which are termed ‘syndromic ASDs.’ Although these syndromes account for a minority of individuals with ASD, an understanding of the genetic causes and associated cellular pathways of these syndromes would provide a molecular foothold to study the aberrant processes that give rise to abnormal social behaviors in ASD. Convergence within the syndromic forms of ASD at the cellular and/or circuit level could provide crucial insights into the pathogenesis and treatment of ASD in the future. Tuberous sclerosis complex (TSC) and fragile X syndrome, caused by mutations in TSC1/TSC2 and FMR1 genes respectively, are two neurogenetic disorders with a high penetrance of ASD; however, the relationship between these two disorders at the cellular level has been controversial and largely remained unexplored.

In previous studies, Mustafa Sahin and his colleagues at Boston Children’s Hospital and Harvard Medical School have shown that both neurons derived from individuals with TSC and neurons from Tsc2-deficient mice have down-regulated expression of the fragile X mental retardation protein (FMRP) and dysregulated expression of FMRP downstream targets1, 2. FMRP negatively regulates the mGluR5 glutamate receptor, and the Sahin lab has previously demonstrated that inhibition of mGluR5 reduces seizures and behavioral deficits seen in Tsc2-mutant mice and decreases the increased protein synthesis seen in Tsc2-deficient neurons2.

In the current study, Sahin will investigate the mechanisms that are responsible for impaired FMRP expression due to the loss of TSC2 in neurons. Sahin will also assess the role of mTOR signaling in this process as TSC1/TSC2 protein complex is known to act via mTOR. Given that dysregulation of TSC, mTOR-signaling and FMRP are all emerging as central components in ASD, the proposed studies will provide crucial insights into the mechanisms by which these genes cause neuronal dysfunction that culminates in abnormal social behaviors in ASD.

References

  1. Sundberg M. et al. Mol. Psychiatry, 23, 2167-2183 (2018) PubMed
  2. Kelly E. et al. Neuropsychopharmacology 43, 1457-1465 (2018) PubMed
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