The role of pathogenic <i>DJ‐1</i> mutations in Parkinson's disease

Abou‐Sleiman, Patrick M.; Healy, Daniel G.; Quinn, Niall; Lees, Andrew J.; Wood, Nicholas W.

doi:10.1002/ana.10675

Cited by 359 publications

(259 citation statements)

References 13 publications

(21 reference statements)

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“…Parkinson's disease [5,29], stimulated expression of the VMAT2 gene and VMAT2 activity. C106 mutant of DJ-1 also reduced stimulating activity toward VMAT2.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Ishikawa

Tanaka

Takahashi-Niki

et al. 2012

Biochemical and Biophysical Research Communications

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Loss-of-functional mutation in the DJ-1 gene causes a subset of familial Parkinson's disease. The mechanism underlying DJ-1-related selective vulnerability in the dopaminergic pathway is, however, not known. Dopamine is synthesized by two enzymes and then packed into synaptic vesicles by vesicular monoamine transporter 2 (VMAT2). In this study, we found that knockdown of DJ-1 expression reduced the levels of mRNA and protein of VMAT2, resulting in reduced VMAT2 activity. Co-immunoprecipitation and pull-down experiments revealed that DJ-1 directly bound to VMAT2, and DJ-1 was co-localized with VMAT2 in cells. Furthermore, ectopic expression of wild-type DJ-1, but not that of L166P, M26I and C106S mutants of DJ-1, increased mRNA and protein levels of VMAT2 and VMAT2 activity. Since VMAT2 and a portion of DJ-1 are localized in the synaptic membrane, these results suggest that DJ-1, but not pathogenically mutated DJ-1, stimulates VMAT2 activity in the synapse by transactivation of the VMAT gene and by direct binding to VMAT2 and that cysteine 106 is necessary for the stimulating activity of DJ-1 toward VMAT2.

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“…Parkinson's disease [5,29], stimulated expression of the VMAT2 gene and VMAT2 activity. C106 mutant of DJ-1 also reduced stimulating activity toward VMAT2.…”

Section: Discussionmentioning

confidence: 99%

“…SH-SY5Y cells harboring a vector backbone were also established. M26I and L166P DJ-1 were found to be as homozygous mutations in Parkinson's disease patients [5,29]. Since cysteine at amino acid number 106 (C106)…”

Section: Stimulation Of Vmat2 Activity By Dj-1mentioning

confidence: 99%

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Ishikawa

Tanaka

Takahashi-Niki

et al. 2012

Biochemical and Biophysical Research Communications

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“…Three other proteins were downregulated in cblC fibroblasts grown in the presence of exogenous HOCbl: DJ-1 (Parkinson ' s disease protein 7), dihydropyrimidase-like 2 (DPYLS2), and annexin V A2 isoform I. DJ-1 belongs to a family of peptidases that act as a positive regulator of androgen receptor-dependent transcription. DJ-1 may also function as a redox-sensitive chaperone and it is thought to protect neurons from oxidative damage [ 92 ]. Defects in this gene are the cause of early-onset Parkinson ' s disease 7 [ 92 , 93 ].…”

Section: Nervous System and Signalingmentioning

confidence: 99%

Proteomics of vitamin B12 processing

Hannibal

DiBello

Jacobsen³

2013

Clinical Chemistry and Laboratory Medicine

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The causes of cobalamin (B 12 , Cbl) deficiency are multifactorial. Whether nutritional due to poor dietary intake, or functional due to impairments in absorption or intracellular processing and trafficking events, the major symptoms of Cbl deficiency include megaloblastic anemia, neurological deterioration and in extreme cases, failure to thrive and death. The common biomarkers of Cbl deficiency (hyperhomocysteinemia and methylmalonic acidemia) are extremely valuable diagnostic indicators of the condition, but little is known about the changes that occur at the protein level. A mechanistic explanation bridging the physiological changes associated with functional B 12 deficiency with its intracellular processers and carriers is lacking. In this article, we will cover the effects of B 12 deficiency in a cblC -disrupted background (also referred to as MMACHC) as a model of functional Cbl deficiency. As will be shown, major protein changes involve the cytoskeleton, the neurological system as well as signaling and detoxification pathways. Supplementation of cultured MMACHC-mutant cells with hydroxocobalamin (HOCbl) failed to restore these variants to the normal phenotype, suggesting that a defective Cbl processing pathway produces irreversible changes at the protein level.

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“…Deletion and point (L166P) mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson disease, PARK7 (2), and other homozygous and heterozygous mutations of DJ-1 have been identified in patients with familial or sporadic Parkinson disease (3)(4)(5)(6). DJ-1 is a multifunctional protein and plays roles in transcriptional regulation and anti-oxidative stress function, and loss of its functions is thought to lead to the onset of Parkinson disease and cancer.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

Ishikawa

Taira

Niki

et al. 2009

Journal of Biological Chemistry

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Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-L-phenylalanine decarboxylase (DDC).DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H 2 O 2 , 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO 2 H and SO 3 H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. Parkinson disease (PD)2 is a neurodegenerative disease that occurs by reduction of the dopamine level through dopaminergic cell death in the substantia nigra. Genetic and environmental factors are thought to be triggers for the onset of PD, but the precise molecular mechanisms are still not known. Dopamine is synthesized by the following two steps: tyrosine is converted to L-DOPA by tyrosine hydroxylase (TH) and then L-DOPA is converted to dopamine by L-dopa decarboxylase (DDC). TH is therefore a key enzyme for dopamine synthesis and is used as a marker for dopaminergic neurons.DJ-1 was first identified by our group as a novel candidate of the oncogene that transformed mouse NIH3T3 cells in cooperation with activated ras (1). Deletion and point (L166P) mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson disease, PARK7 (2), and other homozygous and heterozygous mutations of DJ-1 have been identified in patients with familial or sporadic Parkinson disease (3-6). DJ-1 is a multifunctional protein and plays roles in transcriptional regulation and anti-oxidative stress function, and loss of its functions is thought to lead to the onset of Parkinson disease and cancer. DJ-1 has three cysteine residues at positions 46, 53, and 106 (Cys-46, Cys-53, and Cys-106, respectively), and these cysteine residues are oxidized after cells receive oxidative stress, resulting in scavenging of reactive oxidative species (7-12). Although DJ-1 does not directly bind to DNA, DI-1 acts as a co-activator to activate various transcription factors, including the androgen receptor and p53 tumor suppressor, PSF and Nrf2, by sequestering their inhibitory factors (13-18). The anti-oxidative stress function of DJ-1 is therefore thought to be carried out both by self-oxidation of cysteine residues and by activation of redox-related genes.It has been reported that PSF, a transcription repressor, binds to the promoter region of the TH gene...

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The role of pathogenic DJ‐1 mutations in Parkinson's disease

Cited by 359 publications

References 13 publications

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells

Proteomics of vitamin B12 processing

Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

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