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NOX1 and p53 cross-talk in SCA7 polyglutamine toxicity
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-9064-5432
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-8630-2127
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
neurodegeneration, oxidative stress, NADPH oxidase
National Category
Chemical Sciences Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-119842OAI: oai:DiVA.org:su-119842DiVA: diva2:848819
Available from: 2015-08-26 Created: 2015-08-26 Last updated: 2016-01-29Bibliographically approved
In thesis
1. Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
Open this publication in new window or tab >>Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide expansion in the SCA7 gene resulting in progressive ataxia and retinal dystrophy. SCA7 belongs to a group of neurodegenerative disorders called polyglutamine (polyQ) diseases, that share the common feature of glutamine tract expansions within otherwise unrelated proteins. Common suggested mechanisms by which polyQ expanded proteins induce toxicity include aggregation and induction of oxidative stress. 

In this work we examined the connection between oxidative stress, aggregation and toxicity in SCA7 disease. We show that expression of the SCA7 disease protein, ataxin-7 (ATXN7), results in elevated levels of ROS and oxidative stress which in turn lead to toxicity. Our results also revealed that the oxidative stress further contributes to mutant ATXN7 aggregation. Moreover, we show, for the first time, that the major source of the elevated ROS in mutant ATXN7 cells is the increased activation of NOX1 enzymes. Interestingly, our results further revealed that the increased level of NOX1 activity together with altered p53 function leads to a metabolic shift in mutant ATXN7 expressing cells. Treatments with antioxidants, a NOX1 specific inhibitor or NOX1 knock-down, all decreased the ROS level, restored the metabolic shift and ameliorated the mutant ATXN7 induced toxicity. Taken together, we conclude that mutant ATXN7 activate NOX1 enzymes which results in oxidative stress, increased mutant ATXN7 aggregation, metabolic dysfunction and toxicity. NOX1 specific inhibition could thus be a potential therapeutic strategy for SCA7.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2015. 56 p.
Keyword
neurodegeneration, oxidative stress, NOX, metabolism, p53
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-119846 (URN)978-91-7649-257-4 (ISBN)
Public defence
2015-10-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 09:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2015-09-24 Created: 2015-08-26 Last updated: 2015-09-16Bibliographically approved

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