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Cited by 346

The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.

DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity

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Zhou, Wenbo, Freed, Curt R.·2005·Journal of Biological Chemistry

Abstract

DJ-1 is the third gene that has been linked to Parkinson disease. Mutations in the DJ-1 gene cause early onset PD with autosomal recessive inheritance. To clarify the mechanism of DJ-1 protection, we have overexpressed the gene in cultured dopaminergic cells that were then subjected to chemical stress. In the rat dopaminergic cell line, N27, and in primary dopamine neurons, overexpression of wild type DJ-1 protected cells from death induced by hydrogen peroxide and 6-hydroxydopamine. Overexpressing the L166P mutant DJ-1 had no protective effect. By contrast, knocking down endogenous DJ-1 with antisense DJ-1 rendered cells more susceptible to oxidative damage. We have found that DJ-1 improves survival by increasing cellular glutathione levels through an increase in the rate-limiting enzyme glutamate cysteine ligase. Blocking glutathione synthesis eliminated the beneficial effect of DJ-1. Protection could be restored by adding exogenous glutathione. Wild type DJ-1 reduced cellular reactive oxygen species and reduced the levels of protein oxidation caused by oxidative stress. By a separate mechanism, overexpressing wild type DJ-1 inhibited the protein aggregation and cytotoxicity usually caused by A53T human alpha-synuclein. Under these circumstances, DJ-1 increased the level of heat shock protein 70 but did not change the glutathione level. Our data indicate that DJ-1 protects dopaminergic neurons from oxidative stress through up-regulation of glutathione synthesis and from the toxic consequences of mutant humanalpha-synuclein through increased expression of heat shock protein 70. We conclude that DJ-1 has multiple specific mechanisms for protecting dopamine neurons from cell death.

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Metadata

Authors
Zhou, W., & Freed, C. R.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-12
Volume
280
Issue
52
Pages
43150-43158
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2169466661
Cited by
346
References
51
FWCI
12.91
Type
journal article
Language
en
Open access
hybrid

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CoChat. (2026). Citation check: DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity. https://app.cochat.ai/papers/10.1074/jbc.m507124200
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Zhou, W., & Freed, C. R. (2005). DJ-1 Up-regulates Glutathione Synthesis during Oxidative Stress and Inhibits A53T α-Synuclein Toxicity. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m507124200

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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