Inhibition of Autophagy via p53-Mediated Disruption of ULK1 in a SCA7 Polyglutamine Disease Model [Elektronisk resurs]
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Yu, Xin (författare)
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Muñoz-Alarcón, Andrés (författare)
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Ajayi, Abiodun (författare)
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Webling, Kristin E. (författare)
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Steinhof, Anne (författare)
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- Langel, Ülo (författare)
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Alternativt namn: Langel, Introduction to peptides and proteins
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Ström, Anna-Lena (författare)
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Stockholms universitet Naturvetenskapliga fakulteten (utgivare)
- 2013
- Engelska.
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Ingår i: Journal of Molecular Neuroscience. - 0895-8696. ; 50:3, 586-99
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- 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.
Ämnesord
- Natural Sciences (hsv)
- Chemical Sciences (hsv)
- Naturvetenskap (hsv)
- Kemi (hsv)
- Natural Sciences (hsv)
- Biological Sciences (hsv)
- Naturvetenskap (hsv)
- Biologiska vetenskaper (hsv)
- neurokemi med molekylär neurobiologi (su)
- Neurochemistry with Molecular Neurobiology (su)
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