Hydroxylase Cofactor Activity in Cerebrospinal Fluid of Normal Subjects and Patients with Parkinson's Disease

Lovenberg, Walter; Levine, R.; Robinson, D. C.; Ebert, Michael H.; Williams, Ann C.; Calne, D. B.

doi:10.1126/science.432666

Cited by 139 publications

(56 citation statements)

References 9 publications

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“…It has been shown that BH 4 levels decrease with age in the normal brain (Furukawa and Kish, 1998) and BH 4 levels in the brain and cerebrospinal fluid are lower in PD patients than controls (Lovenberg et al, 1979;Nagatsu et al, 1981). There is conflicting evidence whether BH 4 is protective or toxic to dopaminergic neurons.…”

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…55 In the brains of PD patients, tetrahydrobiopterin has been found at ~50% the level of that found in age-matched controls. 56 It is possible that a reduction in GTPCH might result in the deficiency of biopterin, tetrahydrobiopterin, and/or dopamine. The down-regulation of Punch at both the mRNA and protein levels in PD-model flies suggests that further studies are warranted in order to understand more completely the role(s) of GTPCH in the pathology and etiology of human PD.…”

Section: Pre-symptomatic Disease Stage In Pd-like Drosophila Modelmentioning

confidence: 99%

Protein Expression in a Drosophila Model of Parkinson's Disease

et al. 2006

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Liquid chromatographies coupled to mass spectrometry and database analysis techniques are used to carry out a large-scale proteome characterization for a Drosophila model of Parkinson's disease. Semi-quantitative analysis is performed on A30P α-synuclein expressing transgenic Drosophila and a control lacking the gene at pre-symptomatic, early and advanced disease stages. Changes in gene expression at the level of the proteome are compared with changes reported from published transcriptome measurements. A summary of the comparison indicates that ~44% of transcripts that show changes can also be observed as proteins. However, the patterns of change in protein expression vary substantially compared with the patterns of change observed for corresponding transcripts. In addition, the expression changes of many genes are observed for only transcripts or proteins. Proteome measurements provide evidence for dysregulation of a group of proteins associated with the actin cytoskeleton and mitochondrion at pre-symptomatic and early disease stages that may presage the development of later symptoms. Overall, the proteome measurements provide a view of gene expression that is highly complementary to the insights obtained from the transcriptome.

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“…Decreased formation of ⅐ NOderived metabolites (nitrite and nitrate) in cerebrospinal fluids was observed in PD (15). Furthermore, low levels of tetrahydrobiopterin (BH 4 ) were detected during the onset and progression of PD (2,16,17). BH 4 is a critical cofactor for NOS activity (18,19).…”

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1-Methyl-4-phenylpyridinium-induced Apoptosis in Cerebellar Granule Neurons Is Mediated by Transferrin Receptor Iron-dependent Depletion of Tetrahydrobiopterin and Neuronal Nitric-oxide Synthase-derived Superoxide

Shang

Kotamraju

Kalivendi

et al. 2004

Journal of Biological Chemistry

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In this study, we investigated the molecular mechanisms of toxicity of 1-methyl-4-phenylpyridinium (MPP ؉ Parkinson's disease (PD) 1 is characterized by mitochondrial complex I defects, elevated iron levels in brain tissue, tetrahydrobiopterin (BH 4 ) and dopamine deficiencies, and ␣-synuclein accumulation in Lewy body aggregates (1-4). The exact molecular mechanisms leading to the pathophysiology of PD are not well understood. 1-Methyl-4-phenylpyridinium ion (MPP ϩ ), a mitochondrial complex I inhibitor, produces Parkinson-like symptoms in humans and laboratory animals, and has been used to investigate the mechanism of pathogenesis of PD (5, 6). MPP ϩ is the ultimate metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant found in illicit narcotics (7,8). MPP ϩ is taken up into dopaminergic neurons via the dopamine transporter and accumulates into mitochondria, where it inhibits complex I activity. Although the mechanism of MPP ϩ -induced neurotoxicity is not fully understood, there is increasing evidence supporting the involvement of reactive oxygen species (ROS) and reactive nitrogen species (RNS) (1, 9).)Previous studies using the neuronal nitric-oxide synthase (nNOS) knockout mice implicate nitric oxide ( ⅐ NO) and peroxynitrite (ONOO Ϫ ) in MPP ϩ -induced neurodegeneration (10). However, therapeutic intervention studies with nitric-oxide synthase (NOS) inhibitors in MPTP-treated mice demonstrated the opposite result, i.e. the attenuation of ⅐ NO was more deleterious than protective (11)(12)(13)(14). Decreased formation of ⅐ NOderived metabolites (nitrite and nitrate) in cerebrospinal fluids was observed in PD (15). Furthermore, low levels of tetrahydrobiopterin (BH 4 ) were detected during the onset and progression of PD (2,16,17). BH 4 is a critical cofactor for NOS activity (18,19). Evidence indicates that BH 4 , by acting as a "redox switch," plays a critical role in increasing not only the rate of ⅐ NO generation by NOS, but also in controlling the formation of superoxide and hydrogen peroxide (20 -22). Pharmacological manipulation of BH 4 has been suggested as a therapeutic strategy to modulate ⅐ NO and superoxide generation in neuronal cells and endothelial cells (23)(24)(25)(26)(27). De novo biosynthesis of BH 4 is catalyzed by guanosine 5Ј-triphosphate cyclohydrolase I (GT-PCH I) (28,29). Mammalian cells can also generate BH 4 by

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Hydroxylase Cofactor Activity in Cerebrospinal Fluid of Normal Subjects and Patients with Parkinson's Disease

Cited by 139 publications

References 9 publications

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

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

Protein Expression in a Drosophila Model of Parkinson's Disease

1-Methyl-4-phenylpyridinium-induced Apoptosis in Cerebellar Granule Neurons Is Mediated by Transferrin Receptor Iron-dependent Depletion of Tetrahydrobiopterin and Neuronal Nitric-oxide Synthase-derived Superoxide

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