Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease is a neurodegenerative disorder associated with selective loss of the dopaminergic neurons in the substantia nigra. We have previously shown that tetrahydrobiopterin (BH4), the obligatory cofactor for dopamine synthesis, exerts selective toxicity on dopamine-producing cells. In the present study we determined, both in vitro and in vivo, whether the cell death induced by this endogenous molecule involves apoptosis, resembling that which occurs in Parkinson's disease. Transmission electron microscopic analysis revealed that the dopamine-producing CATH.a cells underwent ultrastructural changes typical of apoptosis, such as cell shrinkage and chromatin condensation, upon exposure to BH4. The BH4 treatment also caused intranuclear DNA fragmentation as determined by TUNEL staining. A similar phenomenon also occurred in vivo, as the nigral cells became TUNEL-positive upon injection of BH4 into the substantia nigra. The BH4-induced CATH.a cell death seemed to involve macromolecule synthesis because cycloheximide and actinomycin D had protective effects. Concurrent treatment with the caspase inhibitor Z-VAD-FMK also suppressed cell death. BH4 treatment led to increases in the ratio of Bax/Bcl-x(L) mRNA and protein levels. Ca(2+) seemed to play a role in BH4-induced cell death, because BH4 caused an increase in Ca(2+) uptake and the intracellular Ca(2+) release blocker dantrolene, intracellular Ca(2+) chelator BAPTA/AM, and extracellular Ca(2+) chelator EGTA each attenuated the toxicity. These data provide evidence that the dopaminergic cell death induced by BH4 involves apoptosis and suggest relevance of this cell death to degeneration of the dopaminergic system in Parkinson's disease.
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PMID:Involvement of apoptosis and calcium mobilization in tetrahydrobiopterin-induced dopaminergic cell death. 1278

Parkinson's disease is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of this cell death is poorly understood, oxidative stress is thought to play a role. We have previously shown that tetrahydrobiopterin (BH4), an obligatory co-factor for tyrosine hydroxylase (TH), exerts selective toxicity on dopamine-producing cells and that this is prevented by antioxidants. This study shows that BH4-induced dopaminergic cell death is primarily mediated by dopamine, evidenced by findings that (i) BH4 toxicity is increased in proportion to cellular dopamine content; (ii) non-dopaminergic cells become susceptible to BH4 upon exposure to dopamine; and (iii) depletion of dopamine attenuates BH4 toxicity in dopamine-producing cells. BH4 causes lipid peroxidation, suggesting involvement of oxidative stress but the toxicity does not require enzymatic oxidation of dopamine. Instead, it seems to involve formation of quinone product(s) because (i) the cell death is attenuated by exposure to or induction of quinone reductase and (ii) BH4-treated cells show increased formation of protein-bound quinones, which is inhibited by thiol antioxidants. These data taken together suggest that the presence of both BH4 and dopamine is important in rendering dopaminergic cells vulnerable and that this involves formation of reactive dopamine quinone products.
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PMID:Dopamine-dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease. 1280 34

We determined whether the preferential toxicity of tetrahydrobiopterin (BH4) on dopamine-producing cells, which we have previously observed in vitro, might also occur in vivo and generate characteristics associated with Parkinson's disease. Intrastriatal BH4 injection caused a loss of tyrosine hydroxylase immunoreactivity and decreased dopamine content. The dopaminergic cell bodies topologically corresponding to the lesioned terminals were selectively degenerated. This was accompanied by a dose-dependent and asymmetric movement deficit in the contralateral forepaw. Direct injection of BH4 into the substantia nigra caused a loss of tyrosine hydroxylase immunoreactivity, but injection into the dorsal raphe was without effect on the GTP cyclohydrolase-immunoreactive serotonergic neurons, demonstrating selectivity for the dopaminergic system. BH4 exhibited a range of potency comparable to that of 6-hydroxydopamine. Thus, this animal model generated by the administration of BH4, the molecule endogenously present in the monoaminergic neurons, exhibited morphological, biochemical, and behavioral characteristics associated with Parkinson's disease and may be useful for studies in dopaminergic degeneration.
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PMID:Degeneration of the nigrostriatal pathway and induction of motor deficit by tetrahydrobiopterin: an in vivo model relevant to Parkinson's disease. 1282 40

Neurodegenerative diseases such as Parkinson's disease exhibit complex features of cell death reflecting both the primary lesion as well as surrounding interconnected events. Because Bcl-2 family members are intimately involved in cell death processes, the present study used dopaminergic cultures from control, Bcl-2-overexpressing, or Bax-deficient genetically modified animals to determine the in situ effects of parkinsonism-inducing toxins. MPP(+)-mediated cell death was attenuated by Bcl-2 but did not require Bax. Accordingly, mutations or deletions within Bax heterodimerization domains, BH1, BH2, or BH3 had no effect on Bcl-2's ability to prevent cell death, whereas the cell-death suppressing BH4 domain did. Although both staurosporine and 6-OHDA induced apoptosis, overexpression of Bcl-2 only rescued cells from programmed cell death induced by staurosporine. Thus, differential cell death pathways are associated with these cytotoxic signals in primary models of Parkinson's disease.
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PMID:Targeted expression of BCL-2 attenuates MPP+ but not 6-OHDA induced cell death in dopaminergic neurons. 1367 65

Parkinson's disease (PD) is a progressive neurologic disease associated with selective degeneration of dopaminergic neurons in the substantia nigra. Despite extensive studies to understand the underlying cause of dopaminergic degeneration, the pathologic factors leading to this neuronal loss in PD remain obscure. We have observed previously that tetrahydrobiopterin (BH4) exerts selective toxicity and oxidative stress on dopaminergic cells, suggesting that BH4 might participate endogenously in dopaminergic neurodegeneration in PD. We investigated signaling events leading to BH4 toxicity in dopaminergic CATH.a cells. We show that c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase (MAPK), is phosphorylated significantly by BH4 exposure. BH4 also leads to c-Jun phosphorylation and an increase in c-Jun protein level. The JNK inhibitor SP600125 protects cells against BH4 toxicity and inhibits cytochrome c release and apoptotic nuclear condensation induced by BH4. These data indicate that activation of the JNK pathway is important in mediating BH4-induced dopaminergic cell death.
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PMID:JNK activation by tetrahydrobiopterin: implication for Parkinson's disease. 1499 47

We have reported previously that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, exerts preferential toxicity on dopamine producing cells. We report in the present study that BH4 injection into the lateral ventricle leads to degeneration of the dopaminergic terminals in the striatum, evidenced by a loss of tyrosine hydroxylase (TH) immunopositive fibers, a decreased amount of TH protein, and decreased dopamine content. Thus, the results of our study further provide evidence that BH4, the molecule endogenously present in the dopaminergic neurons, may participate in the nigrostriatal degeneration as in Parkinson's disease.
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PMID:Loss of striatal dopaminergic fibers after intraventricular injection of tetrahydrobiopterin in rat brain. 1505 Jul 14

Parkinson's disease is a neurodegenerative disorder associated with progressive loss of dopaminergic cells in the substantia nigra. Oxidative stress has been implicated in the pathogenesis of the disease, and dopamine has been suggested as a contributing factor that generates reactive oxygen species due to its unstable catechol moiety. We have previously shown that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, also contributes to the vulnerability of dopamine-producing cells by generating oxidative stress. This study shows that the presence of dopamine in the cytosol enhances the cell's vulnerability to BH4. Upon exposure to ketanserin, a vesicular monoamine transporter inhibitor, BH4-induced dopaminergic cell death is exacerbated, accompanied by increased lipid peroxidation and protein bound quinone. While intracellular amount of DOPAC is elevated by ketanserin, the monoamine oxidase inhibitor pargyline showed no significant protection. Instead, the thiol agent N-acetylcysteine and quinone reductase inducer dimethyl fumarate abolish BH4/ketanserin-induced cell death, suggesting that quinone production plays an important role. Therefore, it can be concluded that the presence of dopamine in the cytosol seems to contribute to the cells' vulnerability to BH4 and that vesicular monoamine transporter plays a protective role in dopaminergic cells by sequestering dopamine not only from monoamine oxidase but also from BH4-induced oxidative stress.
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PMID:Inhibition of vesicular monoamine transporter enhances vulnerability of dopaminergic cells: relevance to Parkinson's disease. 1570 97

Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic system. Brain delivery of glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore the dopaminergic pathway in various animal models of PD. However, GDNF overexpression in the dopaminergic pathway leads to a time-dependent down-regulation of tyrosine hydroxylase (TH), a key enzyme in dopamine synthesis. In order to elucidate GDNF-mediated biochemical effects on dopaminergic neurons, we overexpressed GDNF in the intact rat striatum using a lentiviral vector-mediated gene transfer technique. Long-term GDNF overexpression led to increased GTP cyclohydrolase I (GTPCH I) activity and tetrahydrobiopterin (BH4) levels. Further, we observed a down-regulation of TH enzyme activity in morphologically intact striatal dopaminergic nerve terminals, as well as a significant decrease of dopamine levels in striatal tissue samples. These results indicate that long-term GDNF delivery is a major factor affecting dopamine biosynthesis via a direct or indirect modulation of TH and GTPCH I and further underscore the importance of assessing both GDNF dose and delivery duration prior to clinical application in order to circumvent potentially adverse pharmacological effects on the biosynthesis of dopamine.
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PMID:Long-term glial cell line-derived neurotrophic factor overexpression in the intact nigrostriatal system in rats leads to a decrease of dopamine and increase of tetrahydrobiopterin production. 1593 64

Oxidative stress is believed to contribute to the pathophysiology of Parkinson's disease, in which nigrostriatal dopaminergic (DA) neurons undergo degeneration. Identification of endogenous molecules that contribute to generation of oxidative stress and vulnerability of these cells is critical in understanding the etiology of this disease. Exposure to tetrahydrobiopterin (BH4), the obligatory cofactor for DA synthesis, was observed previously to cause oxidative damage in DA cells. To demonstrate the physiological relevance of this observation, we investigated whether an overproduction of BH4 and DA might actually occur in vivo, and, if it did, whether this might lead to oxidative damage to the nigrostriatal system. Immobilization stress (IMO) elevated BH4 and DA and their synthesizing enzymes, tyrosine hydroxylase and GTP cyclohydrolase I. This was accompanied by elevation of lipid peroxidation and protein-bound quinone, and activities of antioxidant enzymes. These increases in the indices of oxidative stress appeared to be due to increased BH4 synthesis because they were abolished following administration of the BH4 synthesis inhibitor, 2,4-diamino-6-hydroxy-pyrimidine. IMO also caused accumulation of neuromelanin and degeneration of the nigrostriatal system. These results demonstrate that a severe stress can increase BH4 and DA and cause oxidative damages to the DA neurons in vivo, suggesting relevance to Parkinson's disease.
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PMID:Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system. 1618 15

In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS "uncoupling" (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed.
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PMID:Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation. 1619 33


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