ArticleThe Journal of clinical investigation2021
Neddylation stabilizes Nav1.1 to maintain interneuron excitability and prevent seizures in murine epilepsy models.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 49 citations in OpenAlex.
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- Adenylyl Cyclase 8 in Dorsal CA1 Neurons Prevents Depressive-Like Behaviors by Maintaining Neuronal Excitability and Glutamatergic Neurotransmission Through TIP39-PTH2R Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
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- Chronic 40 Hz light flicker mitigates epileptogenesis through a visual pathway associated with the dorsal lateral geniculate nucleus shell.Nature communications · 2025Article
- Regulation of GABAergic neurotransmission by purinergic receptors in brain physiology and disease.Purinergic signalling · 2025Review
- Neddylation steers the fate of cellular receptors.Experimental & molecular medicine · 2024Review
- Neddylation of protein, a new strategy of protein post-translational modification for targeted treatment of central nervous system diseases.Frontiers in neuroscience · 2024Review
- Spatial Distribution of Parvalbumin-Positive Fibers in the Mouse Brain and Their Alterations in Mouse Models of Temporal Lobe Epilepsy and Parkinson's Disease.Neuroscience bulletin · 2023Article
- Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons.Molecular psychiatry · 2023Article
- Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy.Brain : a journal of neurology · 2023Review
- A patient-derived mutation of epilepsy-linked LGI1 increases seizure susceptibility through regulating KCell & bioscience · 2023Article
- Neddylation is required for perinatal cardiac development through stimulation of metabolic maturation.Cell reports · 2023Article
- Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.American journal of human genetics · 2023Article
- Poly-dipeptides produced fromProceedings of the National Academy of Sciences of the United States of America · 2022Article
- The role of gamma oscillations in central nervous system diseases: Mechanism and treatment.Frontiers in cellular neuroscience · 2022Review
- Loss of ARHGAP15 affects the directional control of migrating interneurons in the embryonic cortex and increases susceptibility to epilepsy.Frontiers in cell and developmental biology · 2022Article
- ErbB4 promotes inhibitory synapse formation by cell adhesion, independent of its kinase activity.Translational psychiatry · 2021Article
- Epilepsy channelopathies go neddy: stabilizing NaV1.1 channels by neddylation.The Journal of clinical investigation · 2021Article
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16 authors at 4 institutions in 2 countries.
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Abstract
The excitability of interneurons requires Nav1.1, the α subunit of the voltage-gated sodium channel. Nav1.1 deficiency and mutations reduce interneuron excitability, a major pathological mechanism for epilepsy syndromes. However, the regulatory mechanisms of Nav1.1 expression remain unclear. Here, we provide evidence that neddylation is critical to Nav1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced PVIN excitability and GABA release and consequently increased the network excitability of pyramidal neurons (PyNs). Further analysis revealed a reduction in sodium-current density, not a change in channel property, in mutant PVINs and decreased Nav1.1 protein levels. These results suggest that insufficient neddylation in PVINs reduces Nav1.1 stability and thus the excitability of PVINs; the ensuing increased PyN activity causes seizures in mice. Consistently, Nav1.1 was found reduced by proteomic analysis that revealed abnormality in synapses and metabolic pathways. Our findings describe a role of neddylation in maintaining Nav1.1 stability for PVIN excitability and reveal what we believe is a new mechanism in the pathogenesis of epilepsy.
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