Increased degradation of FMRP contributes to neuronal hyperexcitability in tuberous sclerosis complex

Cell Rep. 2023 Aug 29;42(8):112838. doi: 10.1016/j.celrep.2023.112838. Epub 2023 Jul 25.


Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, but new therapies have been impeded by a lack of understanding of the pathological mechanisms. Tuberous sclerosis complex (TSC) and fragile X syndrome are associated with alterations in the mechanistic target of rapamycin (mTOR) and fragile X messenger ribonucleoprotein 1 (FMRP), which have been implicated in the development of ASD. Previously, we observed that transcripts associated with FMRP were down-regulated in TSC2-deficient neurons. In this study, we find that FMRP turnover is dysregulated in TSC2-deficient rodent primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons and is dependent on the E3 ubiquitin ligase anaphase-promoting complex. We also demonstrate that overexpression of FMRP can partially rescue hyperexcitability in TSC2-deficient iPSC-derived neurons. These data indicate that FMRP dysregulation represents an important pathological mechanism in the development of abnormal neuronal activity in TSC and illustrate a molecular convergence between these two neurogenetic disorders.

Keywords: CP: Neuroscience; autism spectrum disorder; fragile X messenger ribonucleoprotein 1; iPSC-derived neuron; tuberous sclerosis complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder* / metabolism
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Neurons / metabolism
  • Tuberous Sclerosis Complex 2 Protein / metabolism
  • Tuberous Sclerosis* / metabolism


  • Tuberous Sclerosis Complex 2 Protein
  • FMR1 protein, human