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Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
Stockholm University, Faculty of Science, Department of Neurochemistry. (Anna-Lena Ström)ORCID iD: 0000-0001-9064-5432
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 [en]
neurodegeneration, oxidative stress, NOX, metabolism, p53
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-119846ISBN: 978-91-7649-257-4 (print)OAI: oai:DiVA.org:su-119846DiVA: diva2:848898
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
List of papers
1. Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model
Open this publication in new window or tab >>Differential degradation of full-length and cleaved ataxin-7 fragments in a novel stable inducible SCA7 model
2012 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 47, no 2, 219-233 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine repeats, and a common toxic gain-of-function mechanism has been proposed. Proteolytic cleavage of several polyglutamine proteins has been identified and suggested to modulate the polyglutamine toxicity. In this study, we show that full-length and cleaved fragments of the SCA7 disease protein ataxin-7 (ATXN7) are differentially degraded. We found that the ubiquitin-proteosome system (UPS) was essential for the degradation of full-length endogenous ATXN7 or transgenic full-length ATXN7 with a normal or expanded glutamine repeat in both HEK 293T and stable PC12 cells. However, a similar contribution by UPS and autophagy was found for the degradation of proteolytically cleaved ATXN7 fragments. Furthermore, in our novel stable inducible PC12 model, induction of mutant ATXN7 expression resulted in toxicity and this toxicity was worsened by inhibition of either UPS or autophagy. In contrast, pharmacological activation of autophagy could ameliorate the ATXN7-induced toxicity. Based on our findings, we propose that both UPS and autophagy are important for the reduction of mutant ataxin-7-induced toxicity, and enhancing ATXN7 clearance through autophagy could be used as a potential therapeutic strategy in SCA7.

Keyword
Aggregation, Ataxin-7, Autophagy, Polyglutamine, Proteasome, SCA7
National Category
Biological Sciences Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-64160 (URN)10.1007/s12031-012-9722-8 (DOI)000304567700002 ()
Funder
Swedish Research Council, K2010-68X-21449-01-3
Note

AuthorCount: 4;

Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08Bibliographically approved
2. Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model
Open this publication in new window or tab >>Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model
Show others...
2012 (English)In: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 13, 86Article in journal (Refereed) Published
Abstract [en]

Background: Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s) of toxicity is still unclear. Results: In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX) complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Conclusion: Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.

Keyword
Ataxin-7, NADPH oxidase complex, Neurodegeneration, Oxidative stress, Polyglutamine, SCA7
National Category
Chemical Sciences Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-64162 (URN)10.1186/1471-2202-13-86 (DOI)000307239200001 ()
Funder
Swedish Research Council, K2010-68X-21449-01-3
Available from: 2011-11-11 Created: 2011-11-11 Last updated: 2017-12-08Bibliographically approved
3. Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model
Open this publication in new window or tab >>Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model
Show others...
2015 (English)In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, no 4-5, 418-428 p.Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. However, the exact molecular mechanism(s) behind the metabolic dysfunction is still unclear. In this study we identified a previously unreported mechanism, involving disruption of p53 and NADPH oxidase 1 (NOX1) activity, by which the expanded SCA7 disease protein ATXN7 causes metabolic dysregulation. The NOX1 protein is known to promote glycolytic activity, whereas the transcription factor p53 inhibits this process and instead promotes mitochondrial respiration. In a stable inducible PC12 model of SCA7, p53 and mutant ATXN7 co-aggregated and the transcriptional activity of p53 was reduced, resulting in a 50% decrease of key p53 target proteins, like AIF and TIGAR. In contrast, the expression of NOX1 was increased approximately 2 times in SCA7 cells. Together these alterations resulted in a decreased respiratory capacity, an increased reliance on glycolysis for energy production and a subsequent 20% reduction of ATP in SCA7 cells. Restoring p53 function, or suppressing NOX1 activity, both reversed the metabolic dysfunction and ameliorated mutant ATXN7 toxicity. These results hence not only enhance the understanding of the mechanisms causing metabolic dysfunction in SCA7 disease, but also identify NOX1 as a novel potential therapeutic target in SCA7 and possibly other polyQ diseases.

Keyword
Neurodegeneration, NADPH oxidase, Oxidative phosphotylation, Metabolism, p53
National Category
Chemical Sciences Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-116946 (URN)10.1016/j.bbabio.2015.01.012 (DOI)000351793600004 ()25647692 (PubMedID)
Available from: 2015-08-17 Created: 2015-05-04 Last updated: 2017-12-04Bibliographically approved
4. NOX1 and p53 cross-talk in SCA7 polyglutamine toxicity
Open this publication in new window or tab >>NOX1 and p53 cross-talk in SCA7 polyglutamine toxicity
(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
neurodegeneration, oxidative stress, NADPH oxidase
National Category
Chemical Sciences Biological Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-119842 (URN)
Available from: 2015-08-26 Created: 2015-08-26 Last updated: 2016-01-29Bibliographically approved

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