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

Human Molecular Genetics
Kwan Young LeeNien-Pei Tsai

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 phosphorylati...Continue Reading

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Citations

Sep 8, 2020·The EMBO Journal·Jivan KhlghatyanJean-Martin Beaulieu
Dec 22, 2020·Frontiers in Synaptic Neuroscience·Tue G Banke, Andres Barria
Mar 5, 2021·ELife·Inés González-CalvoFekrije Selimi
Sep 17, 2021·Learning & Memory·Felippe E AmorimOlavo B Amaral
Dec 23, 2021·Journal of Neurochemistry·Daphne E LodesNien-Pei Tsai

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