Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the ataxin-3 protein that confers a toxic gain of function. Because of the late onset of the disease, we hypothesize that the accumulated oxidative stress or/and defective antioxidant enzyme ability may be contributory factors in the pathogenesis of MJD. In this study, we utilized SK-N-SH and COS7 cells stably transfected with full-length MJD with 78 polyglutamine repeats to examine any alterations in the antioxidant activity. We demonstrated a significant reduction in the ratio of GSH/GSSG and total glutathione content (GSH + 2x GSSG) in mutant MJD cells compared with the wild-type cells under normal or stressful conditions. We also showed that both SK-N-SH-MJD78 and COS7-MJD78-GFP cell lines have lower activities of catalase, glutathione reductase, and superoxide dismutase compared with the wild-type cell lines. In addition, it is known that, when cells are under oxidative stress, the mitochondrial DNA is prone to damage. Our results demonstrated that mitochondrial DNA copy numbers are decreased in mutant cells and SCA3 patients' samples compared with the normal controls. Furthermore, the amount of common mitochondrial DNA 4,977-bp deletion is higher in SCA3 patients compared with that in normal individuals. Overall, mutant ataxin-3 may influence the activity of enzymatic components to remove O(2)(-) and H(2)O(2) efficiently and promote mitochondrial DNA damage or depletion, which leads to dysfunction of mitochondria. Therefore, we suggest that the cell damage caused by greater oxidative stress in SCA3 mutant cells plays an important role, at least in part, in the disease progression.
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PMID:Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. 1918 26

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.
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PMID:FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3. 2153 89