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)

1-Methyl-4-phenylpyridinium (MPP+) is a mitochondrial Complex I inhibitor and is frequently used to investigate the pathological degeneration of neurons associated with Parkinson's disease (PD). In vitro, extracellular concentration of glucose is one of the most critical factors in establishing the vulnerability of neurons to MPP+ toxicity. While glucose is the primary energy fuel for the brain, central nervous system (CNS) neurons can also take up and utilize other metabolic intermediates for energy. In this study, we compared various monosaccharides, disaccharides, nutritive/non-nutritive sugar alcohols, glycolytic and gluconeogenic metabolic intermediates for their cytoprotection against MPP+ in murine brain neuroblastoma cells. Several monosaccharides were effective against MMP+ (500 microM) including glucose, fructose and mannose, which restored cell viability to 109 +/- 5%, 70 +/- 5%, 99 +/- 3% of live controls, respectively. Slight protective effects were observed in the presence of 3-phosphoglyceric acid and glucose-6-phosphate; however, no protective effects were exhibited by galactose, sucrose, sorbitol, mannitol, glycerol or various gluconeogenic and ketogenic amino acids. On the other hand, fructose 1,6 bisphosphate and gluconeogenic energy intermediates [pyruvic acid, malic acid and phospho(enol)pyruvate (PEP)] were neuroprotective against MPP+. The gluconeogenic intermediates elevated intracellular levels of ATP and reduced propidium iodide (PI) nucleic acid staining to live controls, but did not alter the MPP(+)-induced loss of mitochondrial O2 consumption. These data indicate that malic acid, pyruvic acid and PEP contribute to anaerobic substrate level phosphorylation. The use of hydrazine sulfate to impede gluconeogenesis through PEP carboxykinase (PEPCK) inhibition heightened the protective effects of energy substrates possibly due to attenuated ATP demands from pyruvate carboxylase (PC) activity and pyruvate mitochondrial transport. It was concluded from these studies that several metabolic intermediates are effective in fueling anaerobic glycolysis during mitochondrial inhibition by MPP+.
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PMID:The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity. 1256 89

Several neurological diseases involve focal injury of specific brain structures. Poisons of the electron transport chain complexes (ETCC) can also produce selective injury of brain structures when given systemically and have been implicated in the development of neurological disease. Why ETCC poisons damage particular brain regions is unclear. Calculations of the relative ETCC expression level to glucose utilization rate (GUR) ratio from published observations here reveal that a low ETCC/GUR ratio predisposes a brain structure to injury by a poison of that complex. While GUR can rise with increased neuronal activity, ETCC expression is fixed in the short term. A high ETCC/GUR therefore represents surplus ETCC capacity, allowing for increased ATP generation with short-term increases in demand. A low ETCC/GUR indicates the opposite and will lead to energy failure when the specific ETCC is poisoned. These observations may explain why cyanide, a specific ETCC (IV) inhibitor, can produce selective injury of white matter, which has the lowest ETCC (IV)/GUR found in the brain. They are also consistent with the selective damage of the striatum produced by poisons such as rotenone, a form of injury implicated in Parkinson's disease. The striatum has a low ETCC (I)/GUR ratio, whereas rotenone is a selective ETCC (I) inhibitor.
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PMID:Variations in spare electron transport chain capacity: The answer to an old riddle? 1260

MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson's disease (PD). After sys-temic administration of MPTP, its active metabolite, MPP +, accumulates within SNpc DA neurons, where it inhibits ATP production and stim-ulates superoxide radical formation. The produced superoxide radicals react with nitric oxide (NO) to produce peroxynitrite, a highly reactive tissue-damaging species that damages proteins by oxidation and nitration. Only selected proteins appear nitrated, and among these, is found tyrosine hydroxylase (TH), the rate limiting enzyme in DA synthesis. The process of nitration inactivates TH and, consequently dopamine pro-duction. Peroxynitrite also nicks DNA, which, in turn, activates poly(ADP-ribose) polymerase (PARP). PARP activation consumes ATP, and thus acutely depletes cell energy stores. This latter event aggravates the preexisting energy failure due to MPP + -induced mitochondrial respira-tion blockade and precipitates cell death. Altogether, these findings support the view that MPTP's deleterious cascade of events include mito-chondrial respiration deficit, oxidative stress, and energy failure. Because of the similarity between the MPTP mouse model and PD, it is tempting to propose that a similar scenario applies to the pathogenesis of PD.
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PMID:The parkinsonian toxin MPTP: action and mechanism. 1267 Dec 16

Elevated production of hydrogen peroxide (H2O2) in the central nervous system has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, ischemic reperfusion, stroke, and Alzheimer's disease. Pyruvic acid has a critical role in energy metabolism and a capability to nonenzymatically decarboxylate H2O2 into H2O. This study examined the effects of glycolytic regulation of pyruvic acid on H2O2 toxicity in murine neuroblastoma cells. Glycolytic energy substrates including D-(+)-glucose, D-(-) fructose and the adenosine transport blocker dipyridamole, were not effective in providing protection against H2O2 toxicity, negating energy as a factor. On the other hand, pyruvic acid completely prevented H2O2 toxicity, restoring the loss of ATP and cell viability. H2O2 toxicity was also attenuated by D-fructose 1,6 diphosphate (FBP), phospho (enol) pyruvate (PEP), niacinamide, beta-nicotinamide adenine dinucleotide (beta-NAD+), and reduced form (beta-NADH). Both FBP and PEP exerted positive kinetic effects on pyruvate kinase (PK) activity. Interestingly, only pyruvic acid and beta-NADH exhibited powerful stoichiometric H2O2 antioxidant properties. Further, beta-NADH may exert positive effects on PK activity. Subsequent pyruvic acid accumulation can lead to the recycling of beta-NAD+ through lactate dehydrogenase and beta-NADH through glyceraldehyde-3-phosphate dehydrogenase. It was concluded from these studies that intracellular pyruvic acid and beta-NADH appear to act in concert through glycolysis, to enhance H2O2 intracellular antioxidant capacity in neuroblastoma cells. Future research will be required to examine whether similar effects are observed in primary neuronal culture or intact tissue.
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PMID:Cytoprotection of pyruvic acid and reduced beta-nicotinamide adenine dinucleotide against hydrogen peroxide toxicity in neuroblastoma cells. 1271 24

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of nigra dopaminergic neurons. Lewy bodies (LBs) are a characteristic neuronal inclusion in PD brains. In this study, we report that Dorfin, a RING finger-type ubiquityl ligase for mutant superoxide dismutase-1, was localized with ubiquitin in LBs. Recently, synphilin-1 was identified to associate with alpha-synuclein and to be a major component of LBs. We found that overexpression of synphilin-1 in cultured cells led to the formation of large juxtanuclear inclusions, but showed no cytotoxicity. Dorfin colocalized in these large inclusions with ubiquitin and proteasomal components. In contrast to full-length synphilin-1, overexpression of the central portion of synphilin-1, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding domain, predominantly led to the formation of small punctate aggregates scattered throughout the cytoplasm and showed cytotoxic effects. Dorfin and ubiquitin did not localize in these small aggregates. Overexpression of the N or C terminus of synphilin-1 did not lead to the formation of any aggregates. Dorfin physically bound and ubiquitylated synphilin-1 through its central portion, but did not ubiquitylate wild-type or mutant alpha-synuclein. These results suggest that the central domain of synphilin-1 has an important role in the formation of aggregates and cytotoxicity and that Dorfin may be involved in the pathogenic process of PD and LB formation by ubiquitylation of synphilin-1.
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PMID:Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. 1275 Mar 86

The pre-synaptic protein, alpha-synuclein, has been associated with the pathogenesis of Parkinson's disease. The present study indicates that alpha-synuclein, but not its mutants (A53T, A30P), can protect CNS dopaminergic cells from the parkinsonism-inducing drug 1-methyl-4-phenylpyridinium (MPP+), whereas it cannot protect from the dopaminergic toxin, 6-hydroxydopamine, hydrogen-peroxide, or the beta-amyloid peptide, A-beta. Protection from MPP+ was directly correlated with the preservation of mitochondrial function. Specifically, alpha-synuclein rescued cells from MPP+ mediated decreases in mitochondrial dehydrogenase activity and loss of ATP levels by utilizing ketosis. It also prevented toxin-induced activation of the creatine kinase/creatine phosphate system. Similarly, alpha-synuclein protected cells from the complex I inhibitor rotenone and 3-nitroproprionic acid, a complex II inhibitor. Wild-type alpha-synuclein-mediated neuroprotection and subsequent alterations in energy were not found in dbcAMP-differentiated cells. These results suggest that the normal physiological role for alpha-synuclein may change during development.
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PMID:Alpha-synuclein protects naive but not dbcAMP-treated dopaminergic cell types from 1-methyl-4-phenylpyridinium toxicity. 1280 39

Although the cause of neuronal death in Parkinson's disease (PD) is mainly unknown, growing evidence suggests that both apoptotic and non-apoptotic death may occur in PD. Using primary cultures of mesencephalic dopaminergic neurons and the MN9D dopaminergic neuronal cell line, we attempted to evaluate specifically the existence of the mitochondrial apoptotic pathway, focusing on the mitochondrial release of cytochrome c to the activation of the caspases after 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+) treatment. Both immunofluorescent labeling and immunoblot analysis indicated mitochondrial release of cytochrome c into the cytosol after 6-OHDA or MPP+ treatment. However, the appearance of activated caspase-3 immunoreactivity in tyrosine hydroxylase (TH)-positive neurons was detected only after 6-OHDA. Immunoblot and biochemical analysis also confirmed that activation of both caspase-9 and caspase-3 was induced by 6-OHDA, but not by MPP+. Consequently, cotreatment with a caspase inhibitor (zVAD-fmk) or with an antioxidant (N-acetylcysteine) not only deterred 6-OHDA-induced loss of TH-positive neurons but also abolished the appearance of activated caspase-3 in TH-positive neurons. In contrast, the same treatment did not spare MPP+-treated TH-positive neurons. Interestingly, a reconstitution assay indicated that the addition of ATP to the cytosolic fraction obtained from MPP+-treated cells was sufficient to activate both caspase-9 and caspase-3. Taken together, our results indicate that distinct mechanisms underlie neurotoxin-induced cell death. They also suggest that, after mitochondrial release of cytochrome c in dopaminergic neurons after neurotoxin treatment, intracellular levels of ATP may constitute a critical factor in determining whether a neuron will die by a caspase-dependent or -independent pathway.
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PMID:Caspase-dependent and -independent cell death pathways in primary cultures of mesencephalic dopaminergic neurons after neurotoxin treatment. 1283 30

Experimental models of dopaminergic neurodegeneration play a critical role in our quest to elucidate the cause of Parkinson's disease (PD). Despite the recent development of "genetic models" that have followed upon the discovery of mutations causing rare forms of familial PD, toxic models remain at the forefront when it comes to exploring the pathogenesis of sporadic PD. Among these, the model produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has a competitive advantage over all other toxic models because once this neurotoxin causes intoxication, it induces in humans a syndrome virtually identical to PD. For the past two decades, the complex pharmacology of MPTP and the key steps in the MPTP neurotoxic process have been identified. These molecular events can be classified into three groups: First, those implicated in the initiation of toxicity, which include energy failure due to ATP depletion and oxidative stress mediated by superoxide and nitric oxide; second, those recruited subsequently in response to the initial neuronal perturbations, which include elements of the molecular pathways of apoptosis such as Bax; and, third, those amplifying the neurodegenerative insult, which include various proinflammatory factors such as prostaglandins. Herein, these different contributing factors are reviewed, as is the sequence in which it is believed these factors are acting within the cascade of events responsible for the death of dopaminergic neurons in the MPTP model and in PD. How to target these factors to devise effective neuroprotective therapies for PD is also discussed.
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PMID:The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson's disease. 1284 87

Current hypotheses concerning the mechanism of neuronal cell death in Parkinson's disease (PD) and related synucleopathies propose a functional interaction between parkin and alpha-synuclein (alphaS). Recently parkin was shown to suppress mutant alphaS-induced toxicity in primary neurons, providing a basis for an association between these proteins and neuronal loss [Neuron 36 (2000) 1007-1019]. We have asked if a similar association could be made between wild-type (wt) alphaS and parkin. We examined inducible over-expression of alphaS in SHSY-5Y cells through adenoviral infection under conditions which produce cellular toxicity through a reduction in ATP levels. We demonstrate that parkin suppresses toxicity induced by mutant (A53T) and wt alphaS. Parkin over-expression was also associated with the appearance of higher molecular weight alphaS-immunoreactive bands by Western blot analysis. These data, consistent with a protective role for parkin, extend previous findings to include a functional association between parkin and the wt form of alphaS.
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PMID:Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. 1296 44

ATP-sensitive potassium channels comprise a complex of two structurally different proteins: a member of the inwardly rectifying Kir6 family (Kir6.1 or Kir6.2) and a sulfonylurea receptor (SUR1 or SUR2). Their regulation by intracellular ADP/ATP-concentrations and through various pharmacological agents has profound implications for the excitability of cells and, in the case of neurons, for neurotransmitter release. We previously showed that in rat brain, the Kir6.1 subunit is predominantly expressed in astrocytes in contrast to the Kir6.2 subunit, which is exclusively expressed in neurons. In this report we show, that in addition to the astrocytic expression, the Kir6.1 protein is also found in a small subset of neurons in distinct areas of the brain, like the hypothalamic supraoptic and paraventricular nuclei and the striatum. The Kir6.1-positive neurons in the striatum could be characterized as cholinergic interneurones, verified by immunofluorescence double staining. This complete colocalization of the Kir6.1 subunit in cholinergic interneurons is interesting with respect to the pharmacological potential of these channels. A selective modulation of the Kir6.1 subunit in the cholinergic striatal interneurons may eventually be of therapeutic value for the treatment of Parkinson's disease.
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PMID:The Kir6.1-protein, a pore-forming subunit of ATP-sensitive potassium channels, is prominently expressed by giant cholinergic interneurons in the striatum of the rat brain. 1296 37


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