The Parkinson's disease gene DJ-1 is also a key regulator of stroke-induced damage

Aleyasin, Hossein; Rousseaux, Maxime W.C.; Phillips, Maryam; Kim, Raymond H.; Bland, Ross; Callaghan, Steve; Slack, Ruth S.; During, Matthew J.; Mak, Tak W.; Park, David

doi:10.1073/pnas.0709379104

Cited by 149 publications

(134 citation statements)

References 45 publications

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“…Hence, our work may provide an opportunity to gain further insights into DJ-1 function in the altered neuronal cell response to hypoxia occurring during the early onset Parkinson's disease. In this line, Aleyasin et al (44), already demonstrated that DJ-1 is central to the ability of the brain to respond to stroke (interruption of blood supply due to ischemia or hemorrhagy) as its deficiency sensitizes brains to ischemic damage in vivo, whereas DJ-1 expression does the converse. These data support the hypothesis that Parkinson's disease patients with DJ-1 deficiency could be more sensitive to other neuropathologies such as stroke.…”

Section: Discussionmentioning

confidence: 99%

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Vasseur

Afzal

Tardivel-Lacombe

et al. 2009

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

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In cancer, DJ-1/PARK7 acts as an oncogene that drives Akt-mediated cell survival. Although amplification of DJ-1 has been described in several types of tumors, the mechanistic basis of DJ-1's oncogenic effect remains incompletely understood. A tumor's ability to adapt to hypoxia is absolutely critical for its survival and progression, and this adaptation is largely mediated by the transcription factor HIF1. The stabilization of HIF1 subunits during hypoxia is at least partly dependent on the PI3K/Akt/mTOR pathway. We hypothesized that DJ-1, a positive regulator of Akt when over-expressed, might be involved in regulating HIF1 transcriptional activity under hypoxic conditions. Our results show that loss of DJ-1 in human cell lines and transformed mouse fibroblasts decreases the transcription of a variety of HIF1-responsive genes during hypoxia. Moreover, DJ-1 expression is critical for the Akt and mTOR activities that sustain HIF1 stability. Surprisingly, DJ-1 also regulates the activity of the metabolic sensor AMPK, especially during hypoxia. Finally, DJ-1 appears to protect cells against hypoxia-induced cell death and is required for their adaptation to severe hypoxic stress. Our work positions DJ-1 as an upstream activator of HIF1 function in cancer cells and establishes that DJ-1's oncogenic activity stems from its ability to increase a cell's resistance to hypoxic stress through DJ-1's regulatory effects on mTOR and AMPK. The discovery of these functions of DJ-1 strengthens the case for the development of therapeutics that target DJ-1 activity in cancer cells.mTOR ͉ AMPK ͉ apoptosis

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Section: Discussionmentioning

confidence: 99%

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Vasseur

Afzal

Tardivel-Lacombe

et al. 2009

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

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195

157

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“…Accumulating evidence suggests that alternative mechanisms of action for MPTP, including release of vesicle-stored dopamine and consequent oxidative damage, release of stored iron deposits, increased cytoplasmic calcium and intraneuronal calcium release [94,95] , actually lead to neuronal cell death. Although PD is not typically considered a mitochondrial disease, these studies cited the aforementioned study and other recent work demonstrating that proteins linked to PD affect mitochondrial function or localize to mitochondria [96] , suggesting that mitochondrial dysfunction, especially at complex I, may play a larger role in the development of PD than previously realized.…”

Section: Excitotoxicity In Neurodegenerative Diseasesmentioning

confidence: 99%

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

2009

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A pivotal role for excitotoxicity in neurodegenerative diseases is gaining increasingly more acceptance, but the underlying mechanisms through which it participates in neurodegeneration still need further investigation. Excessive activation of glutamate receptors by excitatory amino acids leads to a number of deleterious consequences, including impairment of calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition and secondary excitotoxicity. Recent studies implicate excitotoxicity in a variety of neuropathological conditions, suggesting that neurodegenerative diseases with distinct genetic etiologies may share excitotoxicity as a common pathogenic pathway. Thus, understanding the pathways involved in excitotoxicity is of critical importance for the future clinical treatment of many neurodegenerative diseases. This review discusses the current understanding of excitotoxic mechanisms and how they are involved in the pathogenesis of neurodegenerative diseases.

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“…In addition, Cys 106 has a low pK a value of 5.4 and therefore exists almost exclusively as the highly reactive cysteine thiolate anion at physiological pH (18). Replacement of Cys 106 with other amino acids in DJ-1 results in a loss of protective activity against oxidative stressors in a number of systems (15,19,20). We have therefore previously suggested that formation of cysteine-sulfinic acid is required for DJ-1 to exert its protective effects (15).…”

mentioning

confidence: 99%

Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1

Blackinton

Lakshminarasimhan

Thomas

et al. 2009

Journal of Biological Chemistry

254

285

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The formation of cysteine-sulfinic acid has recently become appreciated as a modification that links protein function to cellular oxidative status. Human DJ-1, a protein associated with inherited parkinsonism, readily forms cysteine-sulfinic acid at a conserved cysteine residue (Cys 106 in human DJ-1). Mutation of Cys 106 causes the protein to lose its normal protective function in cell culture and model organisms. However, it is unknown whether the loss of DJ-1 protective function in these mutants is due to the absence of Cys 106 oxidation or the absence of the cysteine residue itself. To address this question, we designed a series of substitutions at a proximal glutamic acid residue (Glu 18 ) in human DJ-1 that alter the oxidative propensity of Cys 106 through changes in hydrogen bonding. We show that two mutations, E18N and E18Q, allow Cys 106 to be oxidized to Cys 106 -sulfinic acid under mild conditions. In contrast, the E18D mutation stabilizes a cysteine-sulfenic acid that is readily reduced to the thiol in solution and in vivo. We show that E18N and E18Q can both partially substitute for wild-type DJ-1 using mitochondrial fission and cell viability assays. In contrast, the oxidatively impaired E18D mutant behaves as an inactive C106A mutant and fails to protect cells. We therefore conclude that formation of Cys 106 -sulfinic acid is a key modification that regulates the protective function of DJ-1.Reactive cysteine residues are susceptible to a variety of covalent modifications that are increasingly recognized as a major means of regulating the activities of many proteins (1). Cysteine forms three different species by the direct addition of oxygen; cysteine-sulfenic (-SOH), -sulfinic (-SO 2 H), and -sulfonic (-SO 3 H) acid. Because cysteine can be oxidized to three distinct species, each with different structural and chemical properties, cysteine oxidation is a versatile way for reactive oxygen species (ROS) 4 to alter the activity of a protein.Of the three oxidation products of cysteine, only cysteine-sulfenic acid is readily reduced to the thiol under physiological conditions. However, enzymes that catalyze the ATP-dependent reduction of overoxidized peroxiredoxins containing cysteine-sulfinic acid to cysteine have been discovered and characterized (2, 3). With reversibility comes the potential for cysteine-sulfinic acid modifications to modulate the function of various target proteins in a redox-dependent manner. Therefore, at least in some proteins, cysteine-sulfinic acid should be regarded as a post-translational modification rather than simply a type of protein damage.As expected, many of the proteins that are modified by cysteine oxidation are involved in the oxidative stress response or in the maintenance of cellular redox homeostasis. Of these proteins, DJ-1 has special importance in understanding the role of regulatory cysteine oxidation in neuronal survival. Loss of function mutations in DJ-1 are a rare cause of early onset recessive parkinsonism (4, 5), although the exact function of DJ-1 i...

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The Parkinson's disease gene DJ-1 is also a key regulator of stroke-induced damage

Cited by 149 publications

References 45 publications

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

DJ-1/PARK7 is an important mediator of hypoxia-induced cellular responses

Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases

Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1

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