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Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9064-5432
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9834-4554
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-7746-8574
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-6107-0844
Vise andre og tillknytning
2012 (engelsk)Inngår i: BMC neuroscience (Online), ISSN 1471-2202, E-ISSN 1471-2202, Vol. 13, artikkel-id 86Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
2012. Vol. 13, artikkel-id 86
Emneord [en]
Ataxin-7, NADPH oxidase complex, Neurodegeneration, Oxidative stress, Polyglutamine, SCA7
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-64162DOI: 10.1186/1471-2202-13-86ISI: 000307239200001OAI: oai:DiVA.org:su-64162DiVA, id: diva2:455941
Forskningsfinansiär
Swedish Research Council, K2010-68X-21449-01-3Tilgjengelig fra: 2011-11-11 Laget: 2011-11-11 Sist oppdatert: 2017-12-08bibliografisk kontrollert
Inngår i avhandling
1. STUDIES OF FACTORS AFFECTING INTRACELLULAR TOXICITY OF THE SCA7 DISEASE PROTEIN ATAXIN - 7: FOCUS ON ATAXIN-7 DEGRADATION AND OXIDATIVE STRESS
Åpne denne publikasjonen i ny fane eller vindu >>STUDIES OF FACTORS AFFECTING INTRACELLULAR TOXICITY OF THE SCA7 DISEASE PROTEIN ATAXIN - 7: FOCUS ON ATAXIN-7 DEGRADATION AND OXIDATIVE STRESS
2011 (engelsk)Licentiatavhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expansion of CAG/polyglutamine repeats. Proteins carrying expanded polyglutamine (polyQ) domains are suggested to be resistant to degradation and aggregate. Furthermore, a negative correlation between aggregation and toxicity has been shown. So far, little is known about the turn-over rate and degradation of the SCA7 disease protein ataxin-7 (ATXN7) and how this protein induces cellular toxicity. For the studies in this thesis work, we constructed stable inducible PC12 cell lines expressing GFP-tagged ATXN7 with 10 or 65 glutamines (Qs). Using these cell lines, we studied the turn-over of ATXN7 and the relationship between mutant ATXN7 and oxidative stress.

We showed that ATXN7 with a normal glutamine repeat (ATXN7Q10-GFP) has a short half-life and is mainly degraded by the UPS. In cells expressing expanded ATXN7 (ATXN7Q65-GFP), aggregation and reduced viability was observed. The aggregation increased the half-life of mutant ATXN7. For expanded full-length ATXN7, UPS was still the main degradation pathway; however autophagy also played a role in clearance of soluble ATXN7 fragments and possibly in aggregated ATXN7 material. Moreover, activation of autophagy reduced the level of aggregation and ameliorated the toxicity in cells expressing mutant ATXN7. From this study, we could get the conclusion that although expansion of the polyQ repeat increases the stability of expanded ATXN7, the protein can still be degraded via both UPS and autophagy. Furthermore, stimulation of autophagy could ameliorate the expanded ATXN7 toxicity and could therefore be a potential therapeutic approach for SCA7.

Regarding the role of oxidative stress we showed that expression of mutant ATXN7 leads to increased ROS levels and oxidative stress. Treatment with an antioxidant or blockage of NADPH oxidase complexes (NOX) decreased ATXN7 aggregation, the levels of ROS and ameliorated ATXN7 induced toxicity. Based on these results, we suggest that mutant ATXN7 cause increased ROS production from NOX and antioxidants treatment and or inhibition of NADPH-oxidase might potentially be used as a therapeutic strategy in SCA7.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2011. s. 37
Emneord
Polyglutamine, SCA7, UPS, Autophagy
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-64167 (URN)978-91-7447-410-7 (ISBN)
Presentation
2011-12-09, Heilbronnsalen, Svante Arrhenius väg 21 A, Stockholm, 13:00 (engelsk)
Opponent
Veileder
Merknad

At the time of defence the following paper was unpublished and had a status as follows: Paper 2: Manuscript

Tilgjengelig fra: 2011-11-11 Laget: 2011-11-11 Sist oppdatert: 2015-03-16bibliografisk kontrollert
2. Study of molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
Åpne denne publikasjonen i ny fane eller vindu >>Study of molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
2013 (engelsk)Licentiatavhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2013
Emneord
neurodegeneration, polyglutamine, oxidative stress, metabolism, NADPH oxidase
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-94137 (URN)978-91-637-4122-7 (ISBN)
Presentation
2013-10-23, Heilbronnsalen, Svante Arrhenius väg 21 A, Stockholm, 14:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2013-09-30 Laget: 2013-09-27 Sist oppdatert: 2015-03-09bibliografisk kontrollert
3. Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
Åpne denne publikasjonen i ny fane eller vindu >>Molecular mechanism(s) underlying neurodegeneration in SCA7 disease: Role of NOX enzymes and oxidative stress
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2015. s. 56
Emneord
neurodegeneration, oxidative stress, NOX, metabolism, p53
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-119846 (URN)978-91-7649-257-4 (ISBN)
Disputas
2015-10-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 09:00 (engelsk)
Opponent
Veileder
Merknad

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

Tilgjengelig fra: 2015-09-24 Laget: 2015-08-26 Sist oppdatert: 2019-11-01bibliografisk kontrollert
4. Studies of polyglutamine expanded Ataxin-7 toxicity
Åpne denne publikasjonen i ny fane eller vindu >>Studies of polyglutamine expanded Ataxin-7 toxicity
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant inherited neurodegenerative disease for which there is no cure. SCA7 belongs to the group of polyglutamine disorders, which are all caused by the expansion of a polyglutamine tract in different disease proteins. Common toxic mechanisms have been proposed for polyglutamine diseases; however the exact pathological mechanism(s) are still unclear.

The aim of this thesis was to identify and characterize the molecular mechanisms by which polyglutamine expansion in the ATXN7 protein cause SCA7 and how this can be counteracted. We found that mutant ATXN7 can be degraded by the ubiquitin proteasome system (UPS) and autophagy, the two main cellular degradation pathways. However aggregation stabilized the protein against degradation. Moreover, we found that mutant ATXN7 blocked the induction of autophagy by interfering with p53 and the ULK1-ATG13-FIP200 complex. Pharmacological stimulation of autophagy ameliorated aggregation, as well as toxicity.

We also found that oxidative stress plays an important role in mutant ATXN7 toxicity and that the oxidative stress is generated by activation of NADPH oxidase 1 (NOX1) complexes. Furthermore, we showed that the increased NOX1 activity, together with polyQ expanded ATXN7 mediated disruption of the transcription factor p53, results in metabolic alterations in SCA7 cells. The expression of key p53 regulated metabolic proteins like AIF, TIGAR and GLUT1 was altered in SCA7 cells and resulted in reduced mitochondrial respiration, a higher dependence on glycolysis and reduced ATP levels.

In summary, our data indicate that mutant ATXN7 mediated dysregulation of p53, resulting in autophagic and metabolic alterations, could play a key role in SCA7 and possibly other polyglutamine diseases.

sted, utgiver, år, opplag, sider
Stockholm: Department of Neurochemistry, Stockholm University, 2015. s. 74
Emneord
neurodegeneration, SCA7, protein degradation, aggregation, p53, oxidative stress, NOX
HSV kategori
Forskningsprogram
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-121116 (URN)978-91-7649-249-9 (ISBN)
Disputas
2015-11-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 09:30 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2015-10-22 Laget: 2015-09-24 Sist oppdatert: 2015-10-09bibliografisk kontrollert

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