NOX1 and p53 cross-talk in SCA7 polyglutamine toxicity
(English)Manuscript (preprint) (Other academic)
Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats. Common toxic gain-of-function mechanisms, including oxidative stress and metabolic dysfunction, have been proposed in these disorders. In a recent study we identified increased activity of the ROS producing NADPH oxidase 1 (NOX1) enzyme and reduced activity of the p53 transcription factor as contributing factors to the oxidative stress and metabolic dysfunction in a SCA7 model. In this study we further investigate the molecular mechanisms behind the altered NOX1 and p53 activity, as well as how these two molecules cross-talk to promote oxidative stress, metabolic dysfunction and toxicity in SCA7. We show that increased NOX1 protein stability, as well as alteration of p53-mediated regulation of NOX1 mRNA levels, contributes to the elevated NOX1 expression in SCA7 cells. Furthermore, we show that the enhance NOX1 activity in SCA7 cells is associated with increased oxidation of p53 and promotes a shift in the p53 sub-cellular localization, as well reduction of soluble p53 levels. Taken together, our results suggest that in SCA7 cells a feed-forward loop between NOX1 and p53 is induced. In this loop NOX1-mediated p53 oxidation results in altered p53 localization and reduced p53 transcriptional activity. In turn, the reduced p53 transcriptional activity promotes the activation of NOX1 mRNA and activity. This loop then contributes to the metabolic dysregulation, oxidative stress and toxicity in SCA7 cells.
neurodegeneration, oxidative stress, NADPH oxidase
Chemical Sciences Biological Sciences
Research subject Neurochemistry with Molecular Neurobiology
IdentifiersURN: urn:nbn:se:su:diva-119842OAI: oai:DiVA.org:su-119842DiVA: diva2:848819