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Study of molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0001-9064-5432
2013 (English)Licentiate 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/ATXN7 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 disorders induce toxicity include aggregation and induction of oxidative stress.

In this work, we examined the connection between oxidative stress and toxicity in SCA7 disease. We showed that expression of mutant ataxin-7 (ATXN7) results in elevated level of reactive oxygen species (ROS) and oxidative stress, leading to toxicity. Our results also revealed that the oxidative stress further contributes to mutant ATXN7 aggregation. We showed, for the first time, that the source of the ROS in mutant ATXN7 cells is thorough the activation of the NOX1 enzyme. Interestingly, our results further revealed that the increased level of NOX1 activity and expression by mutant ATXN7 results in a metabolic shift similar to the Warburg effect. Treatments with antioxidants or a NOX1 specific inhibitor decreased the ROS level, restored the metabolic shift and ameliorated the ATXN7 induced toxicity. Taken together, we suggest that mutant ATXN7 specifically activate NOX1 enzyme and that antioxidants treatment or NOX1 specific inhibition could be a potential therapeutic strategy for SCA7.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University , 2013.
Keyword [en]
neurodegeneration, polyglutamine, oxidative stress, metabolism, NADPH oxidase
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-94137ISBN: 978-91-637-4122-7 (print)OAI: oai:DiVA.org:su-94137DiVA: diva2:651895
Presentation
2013-10-23, Heilbronnsalen, Svante Arrhenius väg 21 A, Stockholm, 14:00 (English)
Opponent
Supervisors
Available from: 2013-09-30 Created: 2013-09-27 Last updated: 2015-03-09Bibliographically approved
List of papers
1. 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
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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
2. Polyglutamine expanded ataxin-7 alters NOX1 activity and cellular metabolism
Open this publication in new window or tab >>Polyglutamine expanded ataxin-7 alters NOX1 activity and cellular metabolism
2013 (English)Article in journal (Refereed) Submitted
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ) expansions. Common pathogenic mechanisms, including oxidative stress and metabolic dysfunction, have been implicated in polyQ disease. However, the exact toxic mechanism(s) is still unclear. We have previously demonstrated that expression of the SCA7 disease protein, ATXN7, results in oxidative stress and toxicity via activation of ROS-producing NADPH oxidase (NOX) enzymes. In this study, we show that mutant ATXN7 specifically up-regulates and activates the NOX1 family member. Furthermore, we show that the increased NOX1 activity is linked with a metabolic shift, similar to the Warburg effect, and reduced energy levels. Reduction of the NOX1-mediated ROS production reverse the metabolic shift and rescue the ATXN7 induced toxicity. These data suggest that NOX1-mediated metabolic alterations and energy deficit could play a role in SCA7 pathology and possibly in other polyQ diseases.

Keyword
neurodegeneration, polyglutamine, NADPH oxidase, metabolism
National Category
Chemical Sciences
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-94133 (URN)
Funder
Swedish Research Council, K2010-68X-21449-01-1
Available from: 2013-09-27 Created: 2013-09-27 Last updated: 2017-03-08Bibliographically approved

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