Down‐regulation of heat shock protein 27 in neuronal cells and non‐neuronal cells expressing mutant ataxin‐3

Wen, Feng Chen; Li, Yen Hsien; Tsai, H.-F.; Chao, Lin; Li, Chuan; Liu, Chin San; Lii, Chong‐Kuei; Nukina, Nobuyuki; Hsieh, Meng‐Hsuan

doi:10.1016/s0014-5793(03)00605-7

Cited by 42 publications

(21 citation statements)

References 40 publications

(44 reference statements)

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“…It was recently reported that Bcl-2 regulates an essential pool of mitochondrial GSH and that this regulation may depend on Bcl-2 directly interacting with GSH (Zimmermann et al, 2007). Consistently with these reports, we have previously shown that the levels of Bcl-2 (Tsai et al, 2004;Tien et al, 2008) and Hsp27 (Wen et al, 2003;Chang et al, 2005) in the cells harboring mutant ataxin-3 are significantly lower than those in cells harboring normal ataxin-3. Therefore, our observations could be explained, at least in part, by the decreased levels of Hsp27 and Bcl-2 in cells expressing expanded ataxin-3.…”

Section: Discussionsupporting

confidence: 88%

“…Previous studies have demonstrated that cells stably expressing full-length mutant ataxin-3 do not undergo a rapid form of cell death under basal conditions and thus have likely undergone genetic or biochemical changes that allow them to cope with polyglutamine expansion (Wen et al, 2003;Tien et al, 2008). This observation is consistent with what is expected from the late onset of the disease.…”

Section: Discussionsupporting

confidence: 83%

“…Cell lines SK-N-SH-MJD78, COS7-MJD26-GFP, and COS7-MJD78-GFP were established previously (Wen et al, 2003;Tien et al, 2008). All culturing supplies and transfection materials were obtained from Gibco Life Technologies (Gaithersburg, MD).…”

Section: Methodsmentioning

confidence: 99%

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Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado‐Joseph disease

Kuo

Cheng

et al. 2009

J of Neuroscience Research

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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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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 83%

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Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado‐Joseph disease

Kuo

Cheng

et al. 2009

J of Neuroscience Research

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“…This protein minimizes infarct size, improves contractile function, and attenuates cardiac IR injury [13]. Reduced expression of HSP27 is correlated with poor overall survival [34].…”

Section: Discussionmentioning

confidence: 99%

Glutathione peroxidase 1 protects mitochondria against hypoxia/reoxygenation damage in mouse hearts

Thu

Kim

et al. 2010

Pflugers Arch - Eur J Physiol

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Glutathione peroxidase 1 (GPx1) plays an important role in preventing cardiac dysfunction following ischemia-reperfusion injury. However, its role in protecting cardiac mitochondria against reoxygenation-induced reactive oxygen species (ROS) generation in vivo is unclear. We examined the role of GPx1 in protecting cardiac mitochondria against hypoxia-reoxygenation (HR) damage by testing for alterations in cardiac mitochondrial function. We used a two-dimensional gel electrophoresis proteomics analysis to examine the effects of reoxygenation on cardiac protein in wild-type (GPx1(+/+)) and GPx1 knockout (GPx1(-/-)) mouse hearts. We identified 42 protein spots showing differential expression in the two groups. Sixteen of the proteins identified were located in mitochondria and were involved in a number of key metabolic pathways. To verify our proteomics findings functionally, we performed NADH autofluorescence measurements and ATP production assays. The reduced expression of oxidative phosphorylation proteins in GPx1(-/-) mice following HR treatment resulted in loss of the mitochondrial membrane potential and decreased mitochondrial respiration. Mitochondrial ROS production and oxidative mtDNA damage were increased markedly during reoxygenation in GPx1(-/-) hearts. We also found morphological abnormalities in cardiac mitochondria and myocytes in HR-treated GPx1(-/-). This is the first report of the role of GPx1 in protecting cardiac mitochondria against reoxygenation damage in vivo. These findings will help clarify the mechanisms of HR injury and will aid in the development of antioxidant therapies to prevent cardiac mitochondrial dysfunction associated with reoxygenation.

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“…Lymphoblastoid cells are frequently used as a model to study SCA (Wen et al 2003;Tsai et al 2005). In this study, we examined the length of the SCA8 repeats in ethnic Chinese Parkinson's disease (PD), Alzheimer's disease (AD) and atypical parkinsonism in Taiwan.…”

Section: Introductionmentioning

confidence: 99%

SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

Chen

Soong

et al. 2009

Hum Genet

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Spinocerebellar ataxia type 8 (SCA8) involves bidirectional expression of CUG (ATXN8OS) and CAG (ATXN8) expansion transcripts. The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. In the present study, we assessed the SCA8 repeat size ranges in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism and investigated the genetic variation modulating ATXN8 expression. Thirteen large SCA8 alleles and a novel ATXN8 -62 G/A promoter SNP were found. There is a significant difference in the proportion of the individuals carrying SCA8 larger alleles in atypical parkinsonism (P = 0.044) as compared to that in the control subjects. In lymphoblastoid cells carrying SCA8 large alleles, treatment of MG-132 or staurosporine significantly increases the cell death or caspase 3 activity. Although expressed at low steady-state, ATXN8 expression level is significantly higher (P = 0.012) in cells with SCA8 large alleles than that of the control cells. The ATXN8 transcriptional activity was significantly higher in the luciferase reporter construct containing the -62G allele than that containing the -62A allele in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that ATXN8 gene -62 G/A polymorphism may be functional in modulating ATXN8 expression.

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Down‐regulation of heat shock protein 27 in neuronal cells and non‐neuronal cells expressing mutant ataxin‐3

Cited by 42 publications

References 40 publications

Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado‐Joseph disease

Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado‐Joseph disease

Glutathione peroxidase 1 protects mitochondria against hypoxia/reoxygenation damage in mouse hearts

SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications

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