Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2

Kwan Young Lee, Kathryn A. Jewett, Hee Jung Chung, Nien-Pei Tsai

Research output: Contribution to journalArticle

Abstract

Synaptic scaling allows neurons to homeostatically readjust synaptic strength upon chronic neural activity perturbations. Although altered synaptic scaling has been implicated to underlie imbalanced brain excitability in neurological disorders such as autism spectrum disorders and epilepsy, the molecular dysregulation and restoration of synaptic scaling in those diseases have not been demonstrated. Here, we showed that the homeostatic synaptic downscaling is absent in the hippocampal neurons of Fmr1 KO mice, the mouse model of the most common inherited autism, fragile X syndrome (FXS). We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2. Such dephosphorylation of Nedd4-2 is surprisingly caused by abnormally stable tumor suppressor p53 and subsequently destabilized kinase Akt. Dephosphorylated Nedd4-2 fails to elicit 14-3-3-dependent ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor, and therefore impairs synaptic downscaling. Most importantly, using a pharmacological inhibitor of p53, Nedd4-2 phosphorylation, GluA1 ubiquitination and synaptic downscaling are all restored in Fmr1 KO neurons. Together, our results discover a novel cellular mechanism underlying synaptic downscaling, and demonstrate the dysregulation and successful restoration of this mechanism in the FXS mouse model.

Original languageEnglish (US)
Pages (from-to)2805-2816
Number of pages12
JournalHuman molecular genetics
Volume27
Issue number16
DOIs
StatePublished - Jan 1 2018

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Fragile X Mental Retardation Protein
Ubiquitin-Protein Ligases
Neurons
Fragile X Syndrome
Ubiquitination
Epilepsy
Neoplasms
AMPA Receptors
Autistic Disorder
Nervous System Diseases
Phosphotransferases
Down-Regulation
Phosphorylation
Pharmacology
Brain
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2. / Lee, Kwan Young; Jewett, Kathryn A.; Chung, Hee Jung; Tsai, Nien-Pei.

In: Human molecular genetics, Vol. 27, No. 16, 01.01.2018, p. 2805-2816.

Research output: Contribution to journalArticle

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