1. FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3
- Author
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Susanne Dieringer, Stephanie Dorn, Sybille Krauss, Thomas Klockgether, Katrin Zimmermann, Bernd O. Evert, Ullrich Wuellner, Alexander Pfeifer, Peter Breuer, and Julieta Araujo
- Subjects
Male ,drug effects [Ubiquitination] ,Cell Cycle Proteins ,medicine.disease_cause ,superoxide dismutase 2 ,genetics [Oxidative Stress] ,genetics [Superoxide Dismutase] ,metabolism [Reactive Oxygen Species] ,metabolism [Transcription Factors] ,skin and connective tissue diseases ,genetics [Cell Survival] ,genetics [Ubiquitination] ,Ataxin-3 ,Genetics (clinical) ,genetics [Nerve Tissue Proteins] ,Cells, Cultured ,metabolism [Repressor Proteins] ,chemistry.chemical_classification ,Gene knockdown ,Reverse Transcriptase Polymerase Chain Reaction ,Nuclear Proteins ,genetics [Nuclear Proteins] ,Forkhead Transcription Factors ,General Medicine ,Machado-Joseph Disease ,genetics [Transcription Factors] ,Middle Aged ,Immunohistochemistry ,Cell biology ,cardiovascular system ,Spinocerebellar ataxia ,drug effects [Oxidative Stress] ,RNA Interference ,metabolism [Nuclear Proteins] ,Protein Binding ,medicine.medical_specialty ,Chromatin Immunoprecipitation ,Cell Survival ,drug effects [Cell Survival] ,metabolism [Superoxide Dismutase] ,Blotting, Western ,SOD2 ,FOXO4 protein, human ,Nerve Tissue Proteins ,Biology ,Superoxide dismutase ,pharmacology [Hydrogen Peroxide] ,Internal medicine ,ddc:570 ,genetics [Machado-Joseph Disease] ,Genetics ,medicine ,Humans ,Immunoprecipitation ,Molecular Biology ,Transcription factor ,Reactive oxygen species ,metabolism [Nerve Tissue Proteins] ,Superoxide Dismutase ,ATXN3 protein, human ,Ubiquitination ,Promoter ,Hydrogen Peroxide ,medicine.disease ,Repressor Proteins ,genetics [Repressor Proteins] ,Oxidative Stress ,Endocrinology ,HEK293 Cells ,chemistry ,biology.protein ,metabolism [Machado-Joseph Disease] ,Reactive Oxygen Species ,Oxidative stress ,HeLa Cells ,Transcription Factors - Abstract
Ataxin-3 (ATXN3), the disease protein in spinocerebellar ataxia type 3 (SCA3), binds to target gene promoters and modulates transcription by interaction with transcriptional regulators. Here, we show that ATXN3 interacts with the forkhead box O (FOXO) transcription factor FOXO4 and activates the FOXO4-dependent transcription of the manganese superoxide dismutase (SOD2) gene. Upon oxidative stress, ATXN3 and FOXO4 translocate to the nucleus, concomitantly bind to the SOD2 gene promoter and increase the expression of the antioxidant enzyme SOD2. Compared with normal ATXN3, mutant ATXN3 has a reduced capability to activate the FOXO4-mediated SOD2 expression and interferes with binding of FOXO4 to the SOD2 gene promoter. These findings are consistent with a downregulation of SOD2 in pontine brain tissue and lymphoblastoid cell (LC) lines of SCA3 patients. In response to oxidative stress, LCs from SCA3 patients show a specific impairment to upregulate SOD2 expression in correlation with a significantly increased formation of reactive oxygen species and cytotoxicity. The impairment to increase the expression of SOD2 under oxidative stress conditions is associated with a significantly reduced binding of FOXO4 to the SOD2 gene promoter in SCA3-LCs. Finally and consistent with a regulatory role of ATXN3 in SOD2 expression, knockdown of endogenous ATXN3 by RNA interference represses the expression of SOD2. These findings support that ATXN3 plays an important role in regulating the FOXO4-dependent antioxidant stress response via SOD2 and suggest that a decreased antioxidative capacity and increased susceptibility towards oxidative stress contributes to neuronal cell death in SCA3.
- Published
- 2011