title: Inhibition of autophagy via p53-mediated disruption of ULK1 in a SCA7 polyglutamine disease model.
abstract: 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.
authors.affiliation: Department of Neurochemistry, Stockholm University, 106 91, Stockholm, Sweden. xin.yu@neurochem.su.se
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.forename: Andrés
authors.initials: A
authors.lastname: Muñoz-Alarcón
authors.forename: Abiodun
authors.initials: A
authors.lastname: Ajayi
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Webling
authors.forename: Anne
authors.initials: A
authors.lastname: Steinhof
authors.forename: Ülo
authors.initials: Ü
authors.lastname: Langel
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Ström
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D052160:Benzothiazoles / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D016716:PC12 Cells; D010455:Peptides / Q000187:drug effects / Q000378:metabolism*; D058105:Polymerization / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D052160:Benzothiazoles; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D010455:Peptides; D016159:Tumor Suppressor Protein p53; C097188:polyglutamine; D014050:Toluene; C121565:pifithrin; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human