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Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9834-4554
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0002-1228-9927
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9064-5432
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.ORCID-id: 0000-0001-9671-0354
Visa övriga samt affilieringar
2013 (Engelska)Ingår i: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 50, nr 3, s. 586-99Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains. These so-called polyglutamine (polyQ) diseases are all characterized by aggregation. Reducing the level of aggregating polyQ proteins via pharmacological activation of autophagy has been suggested as a therapeutic approach. However, recently, evidence implicating autophagic dysfunction in these disorders has also been reported. In this study, we show that the SCA7 polyglutamine protein ataxin-7 (ATXN7) reduces the autophagic activity via a previously unreported mechanism involving p53-mediated disruption of two key proteins involved in autophagy initiation. We show that in mutant ATXN7 cells, an increased p53-FIP200 interaction and co-aggregation of p53-FIP200 into ATXN7 aggregates result in decreased soluble FIP200 levels and subsequent destabilization of ULK1. Together, this leads to a decreased capacity for autophagy induction via the ULK1-FIP200-Atg13-Atg101 complex. We also show that treatment with a p53 inhibitor, or a blocker of ATXN7 aggregation, can restore the soluble levels of FIP200 and ULK1, as well as increase the autophagic activity and reduce ATXN7 toxicity. Understanding the mechanism behind polyQ-mediated inhibition of autophagy is of importance if therapeutic approaches based on autophagy stimulation should be developed for these disorders.

Ort, förlag, år, upplaga, sidor
2013. Vol. 50, nr 3, s. 586-99
Nationell ämneskategori
Kemi Biologiska vetenskaper
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
URN: urn:nbn:se:su:diva-91440DOI: 10.1007/s12031-013-0012-xISI: 000320048400022PubMedID: 23592174OAI: oai:DiVA.org:su-91440DiVA, id: diva2:633727
Forskningsfinansiär
Vetenskapsrådet, K2010-68X-21449-01-3
Anmärkning

AuthorCount:7;

Tillgänglig från: 2013-06-27 Skapad: 2013-06-27 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Ingår i avhandling
1. Studies of polyglutamine expanded Ataxin-7 toxicity
Öppna denna publikation i ny flik eller fönster >>Studies of polyglutamine expanded Ataxin-7 toxicity
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Neurochemistry, Stockholm University, 2015. s. 74
Nyckelord
neurodegeneration, SCA7, protein degradation, aggregation, p53, oxidative stress, NOX
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
neurokemi med molekylär neurobiologi
Identifikatorer
urn:nbn:se:su:diva-121116 (URN)978-91-7649-249-9 (ISBN)
Disputation
2015-11-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 09:30 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-10-22 Skapad: 2015-09-24 Senast uppdaterad: 2020-02-27Bibliografiskt granskad

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