Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein

Ying Yang, Yang Geng, Dongyun Jiang, Lin Ning, Hyung Joon Kim, Noo Li Jeon, Anthony Lau, Lu Chen, Michael Z. Lin

Research output: Contribution to journalArticle

Abstract

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP–mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

Original languageEnglish (US)
Pages (from-to)12007-12012
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number24
DOIs
StatePublished - Jun 11 2019

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Keywords

  • BDNF
  • FMRP
  • Fragile X syndrome
  • PSD95
  • mTORC1

ASJC Scopus subject areas

  • General

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