Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson’s disease patients

Takahashi-Niki, Kazuko; Niki, Takeshi; Taira, Takahiro; Iguchi‐Ariga, Sanae M.M.; Ariga, Hiroyoshi

doi:10.1016/j.bbrc.2004.05.187

Cited by 157 publications

(154 citation statements)

References 45 publications

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“…Studies in cell culture and animal models suggest that DJ-1 protein responds to oxidative stress (23)(24)(25)(26)(27)(28)(29)(30)(31)(32), shifting to more acidic species (33,34). This includes oxidation of highly conserved cysteine residues, leading to the formation of cysteine sulfinic or sulfonic acids (35,36).…”

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confidence: 99%

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Meulener

Xu²,

Thomson³

et al. 2006

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

224

191

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Inherited mutations in PARK7 , the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. Like human DJ-1 (hDJ-1), Drosophila DJ-1b protects against oxidative insult and is modified with oxidation. We demonstrate that hDJ-1 rescues flies mutant for DJ-1b, and that a conserved cysteine residue in the fly protein (C104, analogous to C106 in hDJ-1) is critical for biological antioxidant function in vivo . Targeted mutagenesis suggests that modification of DJ-1b at this residue inactivates the protective activity of the protein against oxidative stress. Further studies show that DJ-1 modification increases dramatically with age in flies, mice, and humans, with aged flies showing strikingly increased susceptibility to oxidative stress and markedly enhanced DJ-1b modification upon oxidative challenge. Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson’s disease.

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mentioning

confidence: 99%

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Meulener

Xu²,

Thomson³

et al. 2006

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

224

191

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“…Crystallographic studies of DJ-1 have shown that WT DJ-1 acts as a dimer, and that the L166P mutation inhibits dimer formation by breaking the C-terminal helix (17). When expressed in WT primary neurons, L166P DJ-1 may act as a dominantnegative inhibitor of DJ-1 dimerization such that the WT DJ-1 protein is no longer able to exert its antioxidative effect (41). In PD patients, L166P expression in neurons appears to represent a loss-of-function mutation (9).…”

Section: Discussionmentioning

confidence: 99%

Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress

Kim

Smith

Aleyasin

et al. 2005

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

651

494

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Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1؊͞؊ mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1؊͞؊ embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1؊͞؊ mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults. P arkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, akinesia, and postural instability (1). The cause of PD remains unknown, but epidemiological and genetic studies have suggested that the observed loss of dopaminergic neurons in PD is due to defects in common intracellular signaling pathways (2). Genes linked to familial PD include ␣-synuclein (3), Parkin (4), UCH-L1 (5), PINK1 (6), and dardarin (7). Proteins encoded by these genes are thought to be involved in protein aggregation and proteasome function, processes which, when disrupted in model systems, can also result in noninherited forms of PD (8). Recently, loss-of-function mutations in the DJ-1 locus were found in families with autosomal recessive early-onset PD (9). Additional studies have confirmed other DJ-1 mutations in various PD cohorts (10). DJ-1 was initially cloned as a putative oncogene (11) and as part of an RNA-binding complex (12). DJ-1 is highly expressed by normal astrocytes (13) and has been implicated in fertilization (14) and tumorigenesis (15,16). Studies of the crystal structure of DJ-1 (17) suggest that a particular DJ-1 mutation (L166P) reduces DJ-1 protein stability (18)(19)(20), resulting in degradation through the ubiquitin-proteasome system (21, 22). However, the physiological function of DJ-1 remains largely unknown.Motor impairments in PD patients result from inhibition of the nigrostriatal motor pathway. This inhibition is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (8). The cause of the dopaminergic neuron loss remains unknown, but oxidative stress leading to apoptotic neuronal death has been implicated (23). Various neurotoxic paradigms have been studied in an effort to reproduce oxidative stress leading to neuronal loss in the SNc. Of these, administration of the well characterized meperidine analogue 1-methyl-4-phenyl-1,2,3,6-te...

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“…In addition, the presence of cysteine protease activity of DJ-1 (35) raises an intriguing possibility that DJ-1 could be a SUMO protease. The evolutionally conserved catalytic cysteine residue (Cys-106) is highly sensitive to oxidation (36), and the mutation at this site abolishes its neuroprotective activity (9,37). Although DJ-1 is not highly homologous to other known SUMO proteases, it will be of interest to clarify this possibility.…”

Section: Discussionmentioning

confidence: 99%

DJ-1 Transcriptionally Up-regulates the Human Tyrosine Hydroxylase by Inhibiting the Sumoylation of Pyrimidine Tract-binding Protein-associated Splicing Factor

Zhong

Kim

Rizzu³

et al. 2006

Journal of Biological Chemistry

167

137

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Loss-of-function mutations in DJ-1 cause a subset of familial Parkinson disease (PD). However, the mechanism underlying the selective vulnerability in dopaminergic pathway due to the inactivation of DJ-1 is unclear. Previously, we have reported that DJ-1 is a neuroprotective transcriptional coactivator interacting with the transcriptional co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF). Here we show that DJ-1 and PSF bind and regulate the human tyrosine hydroxylase (TH) promoter. Inactivation of DJ-1 by small interference RNA (siRNA) results in decreased TH expression and L-DOPA production in human dopaminergic cell lines. Consistent with its role as a transcriptional regulator, DJ-1 specifically suppresses the global SUMO-1 modification. High molecular weight sumoylated protein species, including PSF, accumulate in the lymphoblast cells from the patients carrying pathogenic DJ-1 mutations. DJ-1 elevates the TH expression by inhibiting the sumoylation of PSF and preventing its sumoylation-dependent recruitment of histone deacetylase 1. Furthermore, siRNA silencing of DJ-1 decreases the acetylation of TH promoter-bound histones, and histone deacetylase inhibitors restore the DJ-1 siRNA-induced repression of TH. Therefore, our results suggest DJ-1 as a regulator of protein sumoylation and directly link the loss of DJ-1 expression and transcriptional dysfunction to impaired dopamine synthesis. Parkinson disease (PD)4 is a common progressive movement disease characterized by the selective loss of dopaminergic neurons and the decrease of striatal dopamine levels (1). Dopamine deficiency in PD patients contributes to the typical clinical features, which include tremor, bradykinesia, rigidity, and postural instability. These symptoms can be temporally controlled by administering medications targeting dopamine metabolism and function, such as the dopamine precursor L-DOPA and dopamine agonists. The rate-limiting enzyme for dopamine synthesis is tyrosine hydroxylase (TH).Loss-of-function mutations in the DJ-1 gene cause early-onset Parkinsonism (2), although the disease-causing mechanism remains to be fully resolved. The evolutionarily conserved DJ-1 has been shown to regulate oxidative stress, apoptosis, protein aggregation, and transcription in various subcellular compartments (3-8). In vitro experiments from several laboratories have clearly demonstrated the neuroprotective activity of DJ-1, although different molecular mechanisms have been proposed (4, 7-9). The role of DJ-1 in neuronal survival is strengthened by in vivo studies using Drosophila lacking DJ-1, which exhibit increased sensitivity to oxidative stress or environmental mitochondrial toxins (10, 11). In one study, inactivation of a Drosophila DJ-1 homolog by siRNA leads to the degeneration of the TH-positive dopaminergic neurons as in PD patients (10). On the other hand, DJ-1-deficient mice do not reproduce the typical neuropathology of PD patients, such as the loss of the dopaminergic neurons and the formation of intracellu...

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Reduced anti-oxidative stress activities of DJ-1 mutants found in Parkinson’s disease patients

Cited by 157 publications

References 45 publications

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging

Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress

DJ-1 Transcriptionally Up-regulates the Human Tyrosine Hydroxylase by Inhibiting the Sumoylation of Pyrimidine Tract-binding Protein-associated Splicing Factor

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