Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter

Manning-Bog, Amy; Caudle, W. Michael; Perez, Xiomara A.; Reaney, Stephen H.; Paletzki, Ronald F.; Isla, Martha Z.; Chou, Vivian P.; McCormack, Alison L.; Miller, Gary W.; Langston, J. William; Gerfen, Charles R.; Monte, Donato A. Di

doi:10.1016/j.nbd.2007.03.014

“…Typically, higher doses of the toxicant are used to produce robust nigral dopaminergic cell loss and striatal dopamine depletion 23,24,32,[36][37][38]39 . It is important to note that toxicity of MPTP can vary between vendors and lots; consequently doses may need to be adjusted to produce the desired lesion.…”

Section: Discussionmentioning

confidence: 99%

“…Wide use of the MPTP mouse, with paradigms ranging from acute, subacute to chronic [16][17][18] , has allowed for standardization of dosing to result in mild to severe nigrostriatal damage 19,20 with activation of different mechanisms of toxicity depending on the treatment regimen 18,21,22 . Consequently, this permits a 'window of lesioning' to be targeted that may result in enhanced or reduced nigrostriatal injury depending on the therapeutic agent or transgenic model utilized [23][24][25] . Also essential for translational and discovery biology studies are the techniques used to assess damage and the evidence such methods provide.…”

Section: Introductionmentioning

confidence: 99%

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Chou

¹

,

Ko

²

,

Holman

³

et al. 2014

JoVE

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Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer's disease, but its effects in Parkinson's disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone. To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder. Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD. The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates. This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD. Video LinkThe video component of this article can be found at

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“…

Pyrroloquinoline quinone (PQQ) was identified as a redox cofactor of bacterial dehydrogenases 1) and later found to be present in various organisms, including mammals.2-6) PQQ has been shown to act as an anti-oxidant by scavenging superoxide radicals and to protect mitochondria from oxidative stress-induced damage.7) PQQ has also been reported to prevent neuronal cell death in a rodent stroke model [8][9][10][11][12][13][14] and to prevent fibril formation of a-synuclein in vitro.15) The mechanism underlying PQQ activity, however, has not been elucidated.DJ-1 was identified by us as a novel oncogene 16) and later found to be a causative gene for a familial form Parkinson's disease (PD), PARK7.17) DJ-1 is a multi-functional protein and has been shown to play roles in anti-oxidative stress reaction, [18][19][20][21] transcriptional regulation [22][23][24][25][26] and chaperone reaction.27) DJ-1 knockdown cells or DJ-1 knockout mice that had been treated with H 2 O 2 or with several neurotoxins such as MPPϩ, 6-hydroxydopamine (6-OHDA), paraquat, and rotenone became highly susceptible to cell death, [18][19][20][21][28][29][30][31][32][33] and administration of DJ-1 into the substantia nigra of PD model rats that had been treated with 6-OHDA protected the rat against dopaminergic cell death and decreased their locomotion defects.34) It has also been shown that activity of mitochondrial complex 1 was reduced in DJ-1 knockdown cells 19,35) or in DJ-1 knockout mice, 28,29) suggesting that DJ-1 also regulates activity of mitochondrial complex I.DJ-1 has three cysteines located at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively). Of these three cysteines, C106 is the most susceptible to oxidation and is oxidized as SOH, SO 2 H and SO 3 H forms...

…”

mentioning

confidence: 99%

“…27) DJ-1 knockdown cells or DJ-1 knockout mice that had been treated with H 2 O 2 or with several neurotoxins such as MPPϩ, 6-hydroxydopamine (6-OHDA), paraquat, and rotenone became highly susceptible to cell death, [18][19][20][21][28][29][30][31][32][33] and administration of DJ-1 into the substantia nigra of PD model rats that had been treated with 6-OHDA protected the rat against dopaminergic cell death and decreased their locomotion defects.…”

mentioning

confidence: 99%

“…17) DJ-1 is a multi-functional protein and has been shown to play roles in anti-oxidative stress reaction, [18][19][20][21] transcriptional regulation [22][23][24][25][26] and chaperone reaction. 27) DJ-1 knockdown cells or DJ-1 knockout mice that had been treated with H 2 O 2 or with several neurotoxins such as MPPϩ, 6-hydroxydopamine (6-OHDA), paraquat, and rotenone became highly susceptible to cell death, [18][19][20][21][28][29][30][31][32][33] and administration of DJ-1 into the substantia nigra of PD model rats that had been treated with 6-OHDA protected the rat against dopaminergic cell death and decreased their locomotion defects. 34) It has also been shown that activity of mitochondrial complex 1 was reduced in DJ-1 knockdown cells 19,35) or in DJ-1 knockout mice, 28,29) suggesting that DJ-1 also regulates activity of mitochondrial complex I.…”

mentioning

confidence: 99%

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Pyrroloquinoline Quinone Prevents Oxidative Stress-Induced Neuronal Death Probably through Changes in Oxidative Status of DJ-1

Nunome

¹

,

Miyazaki

²

,

Nakano

³

et al. 2008

Biological & Pharmaceutical Bulletin

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Pyrroloquinoline quinone (PQQ) was identified as a redox cofactor of bacterial dehydrogenases 1) and later found to be present in various organisms, including mammals.2-6) PQQ has been shown to act as an anti-oxidant by scavenging superoxide radicals and to protect mitochondria from oxidative stress-induced damage.7) PQQ has also been reported to prevent neuronal cell death in a rodent stroke model [8][9][10][11][12][13][14] and to prevent fibril formation of a-synuclein in vitro.15) The mechanism underlying PQQ activity, however, has not been elucidated.DJ-1 was identified by us as a novel oncogene 16) and later found to be a causative gene for a familial form Parkinson's disease (PD), PARK7.17) DJ-1 is a multi-functional protein and has been shown to play roles in anti-oxidative stress reaction, [18][19][20][21] transcriptional regulation [22][23][24][25][26] and chaperone reaction.27) DJ-1 knockdown cells or DJ-1 knockout mice that had been treated with H 2 O 2 or with several neurotoxins such as MPPϩ, 6-hydroxydopamine (6-OHDA), paraquat, and rotenone became highly susceptible to cell death, [18][19][20][21][28][29][30][31][32][33] and administration of DJ-1 into the substantia nigra of PD model rats that had been treated with 6-OHDA protected the rat against dopaminergic cell death and decreased their locomotion defects.34) It has also been shown that activity of mitochondrial complex 1 was reduced in DJ-1 knockdown cells 19,35) or in DJ-1 knockout mice, 28,29) suggesting that DJ-1 also regulates activity of mitochondrial complex I.DJ-1 has three cysteines located at amino acid numbers 46, 53 and 106 (C46, C53 and C106, respectively). Of these three cysteines, C106 is the most susceptible to oxidation and is oxidized as SOH, SO 2 H and SO 3 H forms.36) Although oxidation at C106 is necessary for exerting activities of DJ-1, [18][19][20]37) it has been reported that highly oxidized DJ-1 at C106 lost its activity 38) and that abnormally oxidized forms of DJ-1 were observed in patients with sporadic forms of PD and Alzheimer's disease. 39,40) In this study, the expression levels and oxidative status at C106 of DJ-1 were examined in human neuroblastoma cell line SH-SY5Y cells treated with H 2 O 2 or 6-OHDA in the presence or absence of PQQ. The results showed that although the expression level of DJ-1 was not changed, the levels of reduced DJ-1 and oxidized DJ-1 at C106 with SOH were increased in cells treated with 6-OHDA and PQQ compared to the level in cells treated with 6-OHDA alone, suggesting that anti-oxidative activity of PQQ is, at least in part, catalyzed by DJ-1 activity. MATERIALS AND METHODSMaterials PQQ was provided by Mitsubishi Gas Chemical Co., Inc. Vitamin C (ascorbic acid) and vitamin E (a-tocopherol) were purchased from Wako Pure Chemical, Japan.Cells and Cell Viability Assay Human SH-SY5Y cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% calf serum. Cells in 96-well plates (5000 cells/well) were cultured with or without various amounts of PQQ, vitamin C or vitam...

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Oxidative Stress and Parkinson Disease

Lim

¹

,

Graham

²

,

Ng

³

2011

Oxidative Stress in Vertebrates and Invertebrates

2

0

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The cause of Parkinson disease is not known at present, and there are many theories as to why the loss of nerve cells that characterises the condition occurs. In recent years, there has been some interest in role of free-radical damage, particularly the damage caused by highly reactive molecules in Parkinson disease and other conditions. In early stages of Parkinsonism, there appears to be a compensatory increase in the number of dopamine receptors to accommodate the initial loss of dopamine neurons. As the disease progress, the number of dopamine receptors decreases, apparently due to concomitant degeneration of dopamine target sites on striatal neurons. The loss of dopaminergic neurons in Parkinson's disease results in enhanced metabolism of dopamine, augmenting the formation of H 2 O 2 , thus leading to generation of highly neurotoxic radicals (OH • ). It has been supposed that degeneration in Parkinson's disease could be a result from the oxidative stress due to dysregulation of dopamine metabolism with consequent free radical formation, depletion of reduced glutathione, a high level of total iron with reduced level of ferritin and deficiency of mitochondrial complex I.

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Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter

Cited by 89 publications

References 47 publications

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Pyrroloquinoline Quinone Prevents Oxidative Stress-Induced Neuronal Death Probably through Changes in Oxidative Status of DJ-1

Oxidative Stress and Parkinson Disease

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