Novel roles of ER stress in repressing neural activity and seizures through Mdm2- and p53-dependent protein translation


Autoři: Dai-Chi Liu aff001;  Daphne E. Eagleman aff002;  Nien-Pei Tsai aff001
Působiště autorů: Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America aff001;  Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America aff002
Vyšlo v časopise: Novel roles of ER stress in repressing neural activity and seizures through Mdm2- and p53-dependent protein translation. PLoS Genet 15(9): e32767. doi:10.1371/journal.pgen.1008364
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008364

Souhrn

Seizures can induce endoplasmic reticulum (ER) stress, and sustained ER stress contributes to neuronal death after epileptic seizures. Despite the recent debate on whether inhibiting ER stress can reduce neuronal death after seizures, whether and how ER stress impacts neural activity and seizures remain unclear. In this study, we discovered that the acute ER stress response functions to repress neural activity through a protein translation-dependent mechanism. We found that inducing ER stress promotes the expression and distribution of murine double minute-2 (Mdm2) in the nucleus, leading to ubiquitination and down-regulation of the tumor suppressor p53. Reduction of p53 subsequently maintains protein translation, before the onset of translational repression seen during the latter phase of the ER stress response. Disruption of Mdm2 in an Mdm2 conditional knockdown (cKD) mouse model impairs ER stress-induced p53 down-regulation, protein translation, and reduction of neural activity and seizure severity. Importantly, these defects in Mdm2 cKD mice were restored by both pharmacological and genetic inhibition of p53 to mimic the inactivation of p53 seen during ER stress. Altogether, our study uncovered a novel mechanism by which neurons respond to acute ER stress. Further, this mechanism plays a beneficial role in reducing neural activity and seizure severity. These findings caution against inhibition of ER stress as a neuroprotective strategy for seizures, epilepsies, and other pathological conditions associated with excessive neural activity.

Klíčová slova:

Action potentials – Drug therapy – Endoplasmic reticulum – Neurons – Protein translation – Stress signaling cascade – Endoplasmic reticulum stress response – Intraperitoneal injections


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