Dopamine‐dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease

Choi, Hyun Jin; Kim, Seong Who; Lee, So Yeon; Hwang, Onyou

doi:10.1046/j.1471-4159.2003.01808.x

Cited by 80 publications

(77 citation statements)

References 62 publications

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“…These results agree with cell-culture models from the same laboratory in which cytotoxicity induced by BH 4 in the culture medium was dependent on the presence of intracellular DA (Choi et al, 2003). In both the cell-culture and rat models, toxicity is associated with high levels of extracellular BH 4 , which leads to compromised membranes; these conditions could reflect those of parkinsonism in later stages of the disease, in which oxidative damage to membranes could allow extracellular leakage of BH 4 .…”

Section: Discussionsupporting

confidence: 87%

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Chaudhuri¹,

Bowling²,

Funderburk³

et al. 2007

J. Neurosci.

194

216

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Catastrophic loss of dopaminergic neurons is a hallmark of Parkinson's disease. Despite the recent identification of genes associated with familial parkinsonism, the etiology of most Parkinson's disease cases is not understood. Environmental toxins, such as the herbicide paraquat, appear to be risk factors, and it has been proposed that susceptibility is influenced by genetic background. The genetic model organism Drosophila is an advantageous system for the identification of genetic susceptibility factors. Genes that affect dopamine homeostasis are candidate susceptibility factors, because dopamine itself has been implicated in neuron damage. We find that paraquat can replicate a broad spectrum of parkinsonian behavioral symptoms in Drosophila that are associated with loss of specific subsets of dopaminergic neurons. In parallel with epidemiological studies that show an increased incidence of Parkinson's disease in males, male Drosophila exhibit paraquat symptoms earlier than females. We then tested the hypothesis that variation in dopamine-regulating genes, including those that regulate tetrahydrobiopterin, a requisite cofactor in dopamine synthesis, can alter susceptibility to paraquatinduced oxidative damage. Drosophila mutant strains that have increased or decreased dopamine and tetrahydrobiopterin production exhibit variation in susceptibility to paraquat. Surprisingly, protection against the neurotoxicity of paraquat is conferred by mutations that elevate dopamine pathway function, whereas mutations that diminish dopamine pools increase susceptibility. We also find that loss-of-function mutations in a negative regulator of dopamine production, Catecholamines-up, delay the onset of neurological symptoms, dopaminergic neuron death, and morbidity during paraquat exposure but confer sensitivity to hydrogen peroxide.

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Section: Discussionsupporting

confidence: 87%

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Chaudhuri¹,

Bowling²,

Funderburk³

et al. 2007

J. Neurosci.

194

216

View full text Add to dashboard Cite

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“…There is conflicting evidence whether BH 4 is protective or toxic to dopaminergic neurons. Extracellular BH 4 has been shown to increase the rate of apoptotic cell death in DA neurons (Choi et al, 2000;Choi et al, 2003;Kim et al, 2004), while intracellular BH 4 appears to protect DA neurons against oxidative damage (Choi et al, 2003;Nakamura et al, 2001). Treatment of cerebellar granule neurons with sepiapterin attenuated 1-methyl-4-phenylpyridinium-induced (MPP+) toxicity (Shang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

et al. 2007

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The PARK3 locus on chromosome 2p13 has shown linkage to both the development and age of onset of Parkinson's disease (PD). One candidate gene at this locus is sepiapterin reductase (SPR). Sepiapterin reductase catalyzes the final step in the biosynthetic pathway of tetrahydrobiopterin (BH 4 ), an essential cofactor for aromatic amino acid hydrolases including tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The expression of SPR was assayed using semiquantitative real-time RT-PCR in human post-mortem cerebellar tissue from neuropathologically confirmed PD cases and neurologically normal controls. The expression of other enzymes involved in BH 4 biosynthesis, including aldose reductase (AKR1B1), carbonyl reductase (CBR1 and CBR3), GTP-cyclohydrolase I (GCH1), and 6-pyruvoyltetrahydrobiopterin (PTS), was also examined. Single-nucleotide polymorphisms around the SPR gene that have been previously reported to show association to PD affection and onset age were genotyped in these samples. Expression of SPR showed a significant 4-fold increase in PD cases relative to controls, while the expression of AKR1B1 and PTS was significantly decreased in PD cases. No difference in expression was detected for CBR1, CBR3, and GCH1. Genetic variants did not show a significant effect on SPR expression, however, this is likely due to the low frequency of rare genotypes in the sample. While the association of SPR to PD is not strong enough to support that this is the PARK3 gene, this study further implicates a role for SPR in idiopathic PD.

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“…Among the proposed underlying causes of DAergic neurodegeneration, oxidative stress is believed to play an important role. Lines of evidence suggest oxidation of DA and consequent quinone modification and oxidative stress as a major factor contributing to the vulnerability of DA cells (Hastings and Zigmond, 1997;Asanuma et al, 2003;Choi et al, 2003a). DA is easily oxidized spontaneously (Hastings and Zigmond, 1997) or enzymatically (Maker et al, 1981) to produce DA quinones.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Sulforaphane against Dopaminergic Cell Death

Han

Lee²,

Lee³

et al. 2007

J Pharmacol Exp Ther

Self Cite

130

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Parkinson's disease (PD) is a progressive neurodegenerative disorder with a selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests oxidation of dopamine (DA) to DA quinone and consequent oxidative stress as a major factor contributing to this vulnerability. We have previously observed that exposure to or induction of NAD(P)H:quinone reductase (QR1), the enzyme that catalyzes the reduction of quinone, effectively protects DA cells. Sulforaphane (SF) is a drug identified as a potent inducer of QR1 in various nonneuronal cells. In the present study, we show that SF protects against compounds known to induce DA quinone production (6-hydroxydopamine and tetrahydrobiopterin) in DAergic cell lines CATH.a and SK-N-BE(2)C as well as in mesencephalic DAergic neurons. SF leads to attenuation of the increase in protein-bound quinone in tetrahydrobiopterin-treated cells, but this does not occur in cells that have been depleted of DA, suggesting involvement of DA quinone. SF pretreatment prevents membrane damage, DNA fragmentation, and accumulation of reactive oxygen species. SF causes increases in mRNA levels and enzymatic activity of QR1 in a dose-dependent manner. Taken together, these results indicate that SF causes induction of QR1 gene expression, removal of intracellular DA quinone, and protection against toxicity in DAergic cells. Thus, this major isothiocyanate found in cruciferous vegetables may serve as a potential candidate for development of treatment and/or prevention of PD.Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of the neurons containing dopamine (DA) in the substantia nigra pars compacta. Among the proposed underlying causes of DAergic neurodegeneration, oxidative stress is believed to play an important role. Lines of evidence suggest oxidation of DA and consequent quinone modification and oxidative stress as a major factor contributing to the vulnerability of DA cells (Hastings and Zigmond, 1997;Asanuma et al., 2003;Choi et al., 2003a). DA is easily oxidized spontaneously (Hastings and Zigmond, 1997) or enzymatically (Maker et al., 1981) to produce DA quinones. The DA quinone species are capable of covalently modifying cellular nucleophiles, including low molecular weight sulfhydryls and protein cysteinyl residues (Graham, 1978). In addition, when in excess, DA quinone cyclizes to become the highly reactive aminochrome, whose redox-cycling leads to generation of superoxide and depletion of cellular NADPH. The detrimental role of DA quinones suggests a requirement for effective mechanisms to remove the cellular quinones. NAD(P)H:quinone reductase (QR1) [DT-diaphorase; NAD(P):H-(quinone acceptor)oxidoreductase; EC 1.6.5.2] is an enzyme that catalyzes two-electron reduction of quinone to the redox-stable hydroquinone (Joseph et al., 2000;Cavelier and Amzel, 2001) and therefore might effectively protect DA cells from quinone-induced damages. A safe and effective inducer of QR1 would be a good candidate with which to p...

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Dopamine‐dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease

Cited by 80 publications

References 62 publications

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Interaction of Genetic and Environmental Factors in aDrosophilaParkinsonism Model

Sepiapterin reductase expression is increased in Parkinson's disease brain tissue

Protective Effect of Sulforaphane against Dopaminergic Cell Death

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