Roles of Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress

Menzies, Fiona M.; Yenisetti, Sarat Chandra; Min, Kyung‐Tai

doi:10.1016/j.cub.2005.07.036

Cited by 187 publications

(151 citation statements)

References 13 publications

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“…Alternatively, PINK1 could functionally collaborate with parkin and DJ-1, two other recessive, early-onset PD-linked genes, to regulate neuronal sensitivity to oxidative stress. In vitro, parkin and DJ-1 have been shown to protect cells from oxidative stress (26)(27)(28)(29)(30)(31). Moreover, PINK1 interacts with DJ-1 and digenic mutations of PINK1 and DJ-1 are associated in early onset familial form of PD (15).…”

Section: Aј-dј and E)mentioning

confidence: 99%

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

Wang

Xiong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

185

140

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Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Mutations in the PINK1 gene are linked to the autosomal recessive early onset familial form of PD. The physiological function of PINK1 and pathological abnormality of PDassociated PINK1 mutants are largely unknown. We here show that inactivation of Drosophila PINK1 (dPINK1) using RNAi results in progressive loss of dopaminergic neurons and in ommatidial degeneration of the compound eye, which is rescued by expression of human PINK1 (hPINK1). Expression of human SOD1 suppresses neurodegeneration induced by dPINK1 inactivation. Moreover, treatment of dPINK1 RNAi flies with the antioxidants SOD and vitamin E significantly inhibits ommatidial degeneration. Thus, dPINK1 plays an essential role in maintaining neuronal survival by preventing neurons from undergoing oxidative stress, thereby suggesting a potential mechanism by which a reduction in PINK1 function leads to PD-associated neurodegeneration.neurodegeneration ͉ oxidative stress ͉ Parkinson's disease ͉ SOD1

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Section: Aј-dј and E)mentioning

confidence: 99%

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

Wang

Xiong

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

185

140

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“…The DJ-1 protein responds to oxidative stress evidenced by a pI shift in sporadic PD (4,5) and in cell (6,7) and animal (8) models. DJ-1 knockout models also show increased sensitivity to toxins that cause mitochondrial dysfunction or oxidative stress (9)(10)(11)(12)(13). Cys-106 of DJ-1, which is oxidized to form a cysteine-sulfinic acid, is critically required for DJ-1 to protect against these types of damage both in vitro (6) and in vivo (12).…”

mentioning

confidence: 99%

RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways

Brug

Blackinton

Chandran

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

201

166

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Parkinson's disease (PD) is a major neurodegenerative condition with several rare Mendelian forms. Oxidative stress and mitochondrial function have been implicated in the pathogenesis of PD but the molecular mechanisms involved in the degeneration of neurons remain unclear. DJ-1 mutations are one cause of recessive parkinsonism, but this gene is also reported to be involved in cancer by promoting Ras signaling and suppressing PTEN-induced apoptosis. The specific function of DJ-1 is unknown, although it is responsive to oxidative stress and may play a role in the maintenance of mitochondria. Here, we show, using four independent methods, that DJ-1 associates with RNA targets in cells and the brain, including mitochondrial genes, genes involved in glutathione metabolism, and members of the PTEN/PI3K cascade. Pathogenic recessive mutants are deficient in this activity. We show that DJ-1 is sufficient for RNA binding at nanomolar concentrations. Further, we show that DJ-1 binds RNA but dissociates after oxidative stress. These data implicate a single mechanism for the pleiotropic effects of DJ-1 in different model systems, namely that the protein binds multiple RNA targets in an oxidation-dependent manner.gene expression ͉ oxidative stress ͉ Parkinson's disease ͉ translation M utations in any of three genes cause a recessively inherited early-onset movement disorder reminiscent of Parkinson's disease (PD). Parkin is an E3 protein-ubiquitin ligase and PINK1 is a mitochondrial kinase (1). Results from Drosophila models suggest that PINK1 and parkin define a single pathway that, when disrupted, leads to mitochondrial damage (2, 3). The third, and rarest, gene for recessive parkinsonism is DJ-1. The DJ-1 protein responds to oxidative stress evidenced by a pI shift in sporadic PD (4, 5) and in cell (6, 7) and animal (8) models. DJ-1 knockout models also show increased sensitivity to toxins that cause mitochondrial dysfunction or oxidative stress (9-13). Cys-106 of DJ-1, which is oxidized to form a cysteine-sulfinic acid, is critically required for DJ-1 to protect against these types of damage both in vitro (6) and in vivo (12). However, the molecular function of DJ-1 is unclear. DJ-1 is part of the ThiJ/PfPI superfamily but the proteins most similar to DJ-1 form a distinct clade away from other members with known function (14, 15), implying a novel activity. As well as effects on oxidation and mitochondrial function, DJ-1 enhances Ras-mediated oncogenesis (16), modulates the PTEN/Akt survival pathway (17,18), suppresses Ask1-mediated apoptosis (19), and increases glutathione (GSH) synthesis, Hsp70 (20) and tyrosine hydroxylase (21, 22) expression. DJ-1 is a small, dimeric, single-domain protein (23), so if all of these effects are true then either the protein has multiple functions or there is a single biochemical activity that explains all of them.One of the original descriptions of the cloning of DJ-1 was as RS, a regulatory component of an RNA binding complex (24). Therefore, we examined whether DJ-1 associates with R...

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“…DJ-1 is conserved in bacteria, plants, animals, and humans (Lucas and Marin, 2007). It is well known that DJ-1 has multiple functions including anti-oxidant and chaperone functions associated with PD pathogenesis (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). However, DJ-1 deficiency or loss-of-function leads to oxidative stressinduced cell death in vitro and in vivo (Chen et al, 2005;Goldberg et al, 2005;Kim et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports have demonstrated that DJ-1 protein protects against neuronal cell death resulting from 6-OHDA-induced ROS. After exposure to dopaminergic neurotoxins including rotenone and 6-OHDA, intracellular ROS levels were inversely correlated with DJ-1 expression levels, suggesting that DJ-1 may mitigate 6-OHDA-induced oxidative stress and help protect cells against oxidative stress (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…It is highly conserved from human to Escherichia coli and is localized in the cytoplasm, nucleus, and mitochondria (Bonifati et al, 2003;Gupta et al, 2008;Lee et al, 2003;Wilson et al, 2004). This protein has multiple functions including antioxidant activity, chaperonelike properties, and transcriptional regulation (Menzies et al, 2005;Xu et al, 2005;Zhou et al, 2006). In addition, it is well known that the loss of the DJ-1 function by oxidative stress and mutation leads to human PD pathogenesis (Bonifati et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

Jeong

Kim

Woo

et al. 2012

Molecules and Cells

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Parkinson's disease (PD) is a well known neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compact (SN). Although the exact mechanism remains unclear, oxidative stress plays a critical role in the pathogenesis of PD. DJ-1 is a multifunctional protein, a potent antioxidant and chaperone, the loss of function of which is linked to the autosomal recessive early onset of PD. Therefore, we investigated the protective effects of DJ-1 protein against SH-SY5Y cells and in a PD mouse model using a cell permeable Tat-DJ-1 protein. Tat-DJ-1 protein rapidly transduced into the cells and showed a protective effect on 6-hydroxydopamine (6-OHDA)-induced neuronal cell death by reducing the reactive oxygen species (ROS). In addition, we found that Tat-DJ-1 protein protects against dopaminergic neuronal cell death in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-induced PD mouse models. These results suggest that Tat-DJ-1 protein provides a potential therapeutic strategy for against ROS related human diseases including PD.

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Roles of Drosophila DJ-1 in Survival of Dopaminergic Neurons and Oxidative Stress

Cited by 187 publications

References 13 publications

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila

RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways

Transduced Tat-DJ-1 Protein Protects against Oxidative Stress-Induced SH-SY5Y Cell Death and Parkinson Disease in a Mouse Model

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