title: Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model.
abstract: Spinocerebellar ataxia type 7 (SCA7) is one of the nine neurodegenerative disorders caused by expanded polyglutamine (polyQ) domains. Common pathogenic mechanisms, including bioenergetics defects, have been suggested for these so called polyQ diseases. However, the exact molecular mechanism(s) behind the metabolic dysfunction is still unclear. In this study we identified a previously unreported mechanism, involving disruption of p53 and NADPH oxidase 1 (NOX1) activity, by which the expanded SCA7 disease protein ATXN7 causes metabolic dysregulation. The NOX1 protein is known to promote glycolytic activity, whereas the transcription factor p53 inhibits this process and instead promotes mitochondrial respiration. In a stable inducible PC12 model of SCA7, p53 and mutant ATXN7 co-aggregated and the transcriptional activity of p53 was reduced, resulting in a 50% decrease of key p53 target proteins, like AIF and TIGAR. In contrast, the expression of NOX1 was increased approximately 2 times in SCA7 cells. Together these alterations resulted in a decreased respiratory capacity, an increased reliance on glycolysis for energy production and a subsequent 20% reduction of ATP in SCA7 cells. Restoring p53 function, or suppressing NOX1 activity, both reversed the metabolic dysfunction and ameliorated mutant ATXN7 toxicity. These results hence not only enhance the understanding of the mechanisms causing metabolic dysfunction in SCA7 disease, but also identify NOX1 as a novel potential therapeutic target in SCA7 and possibly other polyQ diseases.
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: ajayi.abiodun@neurochem.su.se.
authors: Abiodun
authors: A
authors: Ajayi
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: xin.yu@neurochem.su.se.
authors: Xin
authors: X
authors: Yu
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: carro85@hotmail.com.
authors: Carolina
authors: C
authors: Wahlo-Svedin
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: tsirigo3@hotmail.com.
authors: Galateia
authors: G
authors: Tsirigotaki
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: victor.karlstrom@gmail.com.
authors: Victor
authors: V
authors: Karlström
authors: Department of Neurochemistry, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: anna-lena.strom@neurochem.su.se.
authors: Anna-Lena
authors: AL
authors: Ström
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D000067719:Ataxin-7; D015153:Blotting, Western; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005947:Glucose; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid; D053078:Membrane Potential, Mitochondrial; D009154:Mutation / Q000235:genetics; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D010101:Oxygen Consumption; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C494829:AIFM1 protein, human; C000593829:ATXN7 protein, human; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D000067719:Ataxin-7; C000593832:Atxn7 protein, rat; D051272:Glucose Transporter Type 1; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C097188:polyglutamine; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D005947:Glucose
keywords: Metabolism; NADPH oxidase; Neurodegeneration; Oxidative phosphorylation; p53