DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway

Aleyasin, Hossein; Rousseaux, Maxime W.C.; Marcogliese, Paul C.; Hewitt, Sarah J.; Irrcher, Isabella; Joselin, Alvin; Parsanejad, Mohammad; Kim, Raymond H.; Rizzu, Patrizia; Callaghan, Steve; Slack, Ruth S.; Mak, Tak W.; Park, David

doi:10.1073/pnas.0914876107

Cited by 149 publications

(125 citation statements)

References 61 publications

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“…25 Our western blot data show that AKT phosphorylation slightly increased in the early stage of H 2 O 2 treatment (30 min), and it was not influenced by TAT-AM (Supplementary Figure S6), indicating that the protective effect of amino-Nogo-A was unlikely to be mediated by the AKT pathway.…”

Section: Resultsmentioning

confidence: 74%

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

Hou

et al. 2012

Cell Death Differ

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Nogo-A is originally identified as an inhibitor of axon regeneration from the CNS myelin. Nogo-A is mainly expressed by oligodendrocytes, and also by some neuronal subpopulations, particularly in the developing nervous system. Although extensive studies have uncovered regulatory roles of Nogo-A in neurite outgrowth inhibition, precursor migration, neuronal homeostasis, plasticity and neurodegeneration, its cell-autonomous functions in neurons are largely uncharacterized. Here, we show that HIV-1 trans-activating-mediated amino-Nogo-A protein transduction into cultured primary cortical neurons achieves an almost complete neuroprotection against oxidative stress induced by exogenous hydrogen peroxide (H 2 O 2 ). Endogenously expressed neuronal Nogo-A is significantly downregulated upon H 2 O 2 treatment. Furthermore, knockdown of Nogo-A results in more susceptibility to acute oxidative insults and markedly increases neuronal death. Interacting with peroxiredoxin 2 (Prdx2), amino-Nogo-A reduces reactive oxygen species (ROS) generation and extracellular signal-regulated kinase phosphorylation to exert neuroprotective effects. Structure-function mapping experiments reveal that, out of NiG-D20, a novel region comprising residues 290-562 of amino-Nogo-A is indispensable for preventing oxidative neuronal death. Moreover, mutagenesis analysis confirms that cysteine residues 424, 464 and 559 are involved in the inhibition of ROS generation and neuroprotective role of amino-Nogo-A. Our data suggest that neuronal Nogo-A might play a cell-autonomous role in improving neuronal survival against oxidative insult through interacting with Prdx2 and scavenging of ROS.

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Section: Resultsmentioning

confidence: 74%

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

Hou

et al. 2012

Cell Death Differ

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“…Dysfunction of wild-type DJ-1 as a result of destabilizing oxidative modifications is also thought to play a role in more common sporadic forms of PD (13)(14)(15). DJ-1 has been reported to suppress neurodegeneration in cellular and animal models by activating antioxidant responses (16 -21), up-regulating or carrying out a molecular chaperone function (20 -24), and/or inducing prosurvival signaling responses (12,19,25). DJ-1 is a homodimer (subunit molecular weight ϭ 20 kDa) for which there is evidence that cysteine 106 (C106) in the subunit sequence is readily oxidized to the sulfinic acid under oxidizing conditions, yielding the "2O" form of the protein (14,16,17,26).…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%

Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Madian

Hindupur

Hulleman

et al. 2012

Molecular & Cellular Proteomics

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Mutations in the gene encoding DJ-1 have been identified in patients with familial Parkinson's disease (PD) and are thought to inactivate a neuroprotective function. Oxidation of the sulfhydryl group to a sulfinic acid on cysteine residue C106 of DJ-1 yields the "2O " form, a variant of the protein with enhanced neuroprotective function. We hypothesized that some familial mutations disrupt DJ-1 activity by interfering with conversion of the protein to the 2O form. To address this hypothesis, we developed a novel quantitative mass spectrometry approach to measure relative changes in oxidation at specific sites in mutant DJ-1 as compared with the wild-type protein. Treatment of recombinant wild-type DJ-1 with a 10-fold molar excess of H 2 O 2 resulted in a robust oxidation of C106 to the sulfinic acid, whereas this modification was not detected in a sample of the familial PD mutant M26I exposed to identical conditions. Methionine oxidized isoforms of wild-type DJ-1 were depleted, presumably as a result of misfolding and aggregation, under conditions that normally promote conversion of the protein to the 2O form. These data suggest that the M26I familial substitution and methionine oxidation characteristic of sporadic PD may disrupt DJ-1 function by disfavoring a site-specific modification required for optimal neuroprotective activity. Our findings indicate that a single amino acid substitution can markedly alter a protein's ability to undergo oxidative modification, and they imply that stimulating the

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“…DJ-1 (CAP1/RS/PARK7) is a protein described as a protector against oxidative stress in neurons, and is largely documented for its association with Parkinson's disease (Kahle et al, 2009;Aleyasin et al, 2010;Giaime et al, 2010;Guzman et al, 2010;Hao et al, 2010). DJ-1 is also referred to as an oncogene and found to be overexpressed in many types of tumors (Hinkle et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Consequences of DJ-1 upregulation following p53 loss and cell transformation

et al. 2011

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p53 is a tumor suppressor that responds to various stress signals by initiating cell-cycle arrest, senescence and apoptosis. Mutations of the p53 gene are found in over 50% of human tumors, highlighting the importance of p53 in tumor suppression. Numerous studies have reported on the interactions between p53, IGF-1-AKT and mTOR pathways as potentially explaining some of the tumor suppressive activities of p53. To further understand the basis of these interactions, we analyzed the involvement of DJ-1, an oncogene known to drive AKT-mediated cell survival, in the p53-AKT axis. In this study, we show that DJ-1 and p53 are tightly 'linked': p53 prevents the accumulation of DJ-1 protein, whereas loss of p53 leads to stabilization and enhancement of DJ-1 expression. Interestingly, this increase in DJ-1 level is only observed when p53 loss is accompanied by transformation of cells. Moreover, DJ-1 seems to be required for the enhanced activation of AKT observed in p53-deficient cells. Such observation confers a new property to DJ-1 associated to transforming-process to its oncogenic ability to drive AKT activation. We also show that DJ-1 is necessary for p53 activation following oxidative stress, suggesting the existence of a finely regulated loop between these two proteins in transformed cells. Finally, we demonstrate that in the absence of p53, DJ-1 is stabilized by ROS accumulation, and surprisingly seems to be required for this high intracellular ROS production. These data offer new insights into the regulation of DJ-1 and suggest that DJ-1 is a target of p53. Importantly, our study highlights that during transformation, DJ-1 is having a key role in the p53-regulated AKT pathway and p53-driven oxidative-stress response.

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DJ-1 protects the nigrostriatal axis from the neurotoxin MPTP by modulation of the AKT pathway

Cited by 149 publications

References 61 publications

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

Effect of Single Amino Acid Substitution on Oxidative Modifications of the Parkinson’s Disease-Related Protein, DJ-1

Consequences of DJ-1 upregulation following p53 loss and cell transformation

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