ArticleHuman molecular genetics2018
Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 43 citations in OpenAlex.
- Neuroligin-2 is ubiquitinated by Nedd4l to control developmental astrocyte morphogenesis.The Journal of cell biology · 2026Article
- E3 Ubiquitin Ligase Nedd4-2 Exacerbates Seizure-Induced Mitochondrial Defects in an Alzheimer's Disease Mouse Model.Journal of neurochemistry · 2026Article
- Neuroligin-2 is ubiquitinated by Nedd4l to control developmental astrocyte morphogenesis.bioRxiv : the preprint server for biology · 2025Article
- Impairment in the homeostatic recruitment of layer 5/6 neurons following whisker stimulation in Fmr1 KO mice.Neurobiology of disease · 2025Article
- Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome.International journal of molecular sciences · 2024Article
- mGluR7 allosteric modulator AMN082 corrects protein synthesis and pathological phenotypes in FXS.EMBO molecular medicine · 2024Article
- A human in vitro neuronal model for studying homeostatic plasticity at the network level.Stem cell reports · 2023Article
- Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning.Molecular psychiatry · 2023Article
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- E3 ubiquitin ligase Nedd4-2 exerts neuroprotective effects during endoplasmic reticulum stress.Journal of neurochemistry · 2022Article
- Genetic Deficiency of p53 Leads to Structural, Functional, and Synaptic Deficits in Primary Somatosensory Cortical Neurons of Adult Mice.Frontiers in molecular neuroscience · 2022Article
- Infantile spasms-linked Nedd4-2 mediates hippocampal plasticity and learning via cofilin signaling.EMBO reports · 2021Article
- Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?Learning & memory (Cold Spring Harbor, N.Y.) · 2021Article
- ER stress-induced modulation of neural activity and seizure susceptibility is impaired in a fragile X syndrome mouse model.Neurobiology of disease · 2021Article
- Historical perspective and progress on protein ubiquitination at glutamatergic synapses.Neuropharmacology · 2021Review
- AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats.Biomedicines · 2021Article
- Unbiased proteomic screening identifies a novel role for the E3 ubiquitin ligase Nedd4-2 in translational suppression during ER stress.Journal of neurochemistry · 2021Article
- Article
- Hyperexcitability and Homeostasis in Fragile X Syndrome.Frontiers in molecular neuroscience · 2021Article
- Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions.Frontiers in cellular neuroscience · 2021Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.