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 (PD) is a neurologic disorder characterized by dopaminergic cell death in the substantia nigra. PD pathogenesis involves mitochondrial dysfunction, proteasome impairment, and alpha-synuclein aggregation, insults that may be especially toxic to oxidatively stressed cells including dopaminergic neurons. The enzyme methionine sulfoxide reductase A (MsrA) plays a critical role in the antioxidant response by repairing methionine-oxidized proteins and by participating in cycles of methionine oxidation and reduction that have the net effect of consuming reactive oxygen species. Here, we show that MsrA suppresses dopaminergic cell death and protein aggregation induced by the complex I inhibitor rotenone or mutant alpha-synuclein, but not by the proteasome inhibitor MG132. By comparing the effects of MsrA and the small-molecule antioxidants N-acetylcysteine and vitamin E, we provide evidence that MsrA protects against PD-related stresses primarily via methionine sulfoxide repair rather than by scavenging reactive oxygen species. We also demonstrate that MsrA efficiently reduces oxidized methionine residues in recombinant alpha-synuclein. These findings suggest that enhancing MsrA function may be a reasonable therapeutic strategy in PD.
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PMID:Methionine sulfoxide reductase A protects dopaminergic cells from Parkinson's disease-related insults. 1845 2

Metal ions are believed to participate in many neurodegenerative conditions. In excitotoxic cell death there is convincing evidence for the participation of Ca(2+) and Zn(2+) ions although the exact molecular mechanisms by which these metals exert their effects are unclear. Only in one instance has the metal binding site of metalloenzymes been exploited for therapeutic purposes and this is the use of Li(+) in the treatment of bipolar affective disorder. Again the exact molecular target is not clear but is likely to involve a Mg(2+)-dependent enzyme of an intracellular signalling pathway. In Parkinson's disease, the selective loss of dopaminergic neurones in the substantia nigra may be caused by radical-mediated damage and there is good evidence to suggest that Fe(2+) or (3+) is important in promoting formation of radical species. The evidence that free radicals are important in mediating other neurodegenerative conditions is less strong but still substantial enough to suggest that removal of reactive oxygen species or preventing their formation may be a valid approach to therapy.
Met Based Drugs 1997
PMID:Metal ions in neuroscience. 1847 82

Catechol O-methyltransferase (COMT) plays important roles in the metabolism of catecholamine neurotransmitters and catechol estrogens. The development of COMT inhibitors for use in the treatment of Parkinson's disease has been aided by crystallographic structures of the rat enzyme. However, the human and rat proteins have significantly different substrate specificities. Additionally, human COMT contains a common valine-methionine polymorphism at position 108. The methionine protein is less stable than the valine polymorph, resulting in decreased enzyme activity and protein levels in vivo. Here we describe the crystal structures of the 108V and 108M variants of the soluble form of human COMT bound with S-adenosylmethionine (SAM) and a substrate analog, 3,5-dinitrocatechol. The polymorphic residue 108 is located in the alpha5-beta3 loop, buried in a hydrophobic pocket approximately 16 A from the SAM-binding site. The 108V and 108M structures are very similar overall [RMSD of C(alpha) atoms between two structures (C(alpha) RMSD)=0.2 A], and the active-site residues are superposable, in accord with the observation that SAM stabilizes 108M COMT. However, the methionine side chain is packed more tightly within the polymorphic site and, consequently, interacts more closely with residues A22 (alpha2) and R78 (alpha4) than does valine. These interactions of the larger methionine result in a 0.7-A displacement in the backbone structure near residue 108, which propagates along alpha1 and alpha5 toward the SAM-binding site. Although the overall secondary structures of the human and rat proteins are very similar (C(alpha) RMSD=0.4 A), several nonconserved residues are present in the SAM-(I89M, I91M, C95Y) and catechol- (C173V, R201M, E202K) binding sites. The human protein also contains three additional solvent-exposed cysteine residues (C95, C173, C188) that may contribute to intermolecular disulfide bond formation and protein aggregation.
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PMID:Crystal structures of human 108V and 108M catechol O-methyltransferase. 1848 44

alpha-Synuclein is the major component of the intracellular Lewy body inclusions present in Parkinson disease (PD) neurons. PD involves the loss of dopaminergic neurons in the substantia nigra and the subsequent depletion of dopamine (DA) in the striatum. DA can inhibit alpha-synuclein fibrillization in vitro and promote alpha-synuclein aggregation into soluble oligomers. We have studied the mechanism by which DA mediates alpha-synuclein aggregation into soluble oligomers. Reacting alpha-synuclein with DA increased the mass of alpha-synuclein by 64 Da. NMR showed that all four methionine residues were oxidized by DA, consistent with the addition of 64 Da. Substituting all four methionines to alanine significantly reduced the formation of DA-mediated soluble oligomers. The (125)YEMPS(129) motif in alpha-synuclein can modulate DA inhibition of alpha-synuclein fibrillization. However, alpha-synuclein ending before the (125)YEMPS(129) motif (residues 1-124) could still form soluble oligomers. The addition of exogenous synthetic YEMPS peptide inhibited the formation of soluble oligomers and resulted in the YEMPS peptide being oxidized. Therefore, the (125)YEMPS(129) acts as an antioxidant rather than interacting directly with DA. Our study defines methionine oxidation as the dominant mechanism by which DA generates soluble alpha-synuclein oligomers and highlights the potential role for oxidative stress in modulating alpha-synuclein aggregation.
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PMID:Formation of dopamine-mediated alpha-synuclein-soluble oligomers requires methionine oxidation. 1924 30

Parkinson disease (PD)-associated genomic deletions and the destabilizing L166P point mutation lead to loss of the cytoprotective DJ-1 protein. The effects of other PD-associated point mutations are less clear. Here we demonstrate that the M26I mutation reduces DJ-1 expression, particularly in a null background (knockout mouse embryonic fibroblasts). Thus, homozygous M26I mutation causes loss of DJ-1 protein. To determine the cellular consequences, we measured suppression of apoptosis signal-regulating kinase 1 (ASK1) and cytotoxicity for [M26I]DJ-1, and systematically all other DJ-1 methionine and cysteine mutants. C106A mutation of the central redox site specifically abolished binding to ASK1 and the cytoprotective activity of DJ-1. DJ-1 was apparently recruited into the ASK1 signalosome via Cys-106-linked mixed disulfides. The designed higher order oxidation mimicking [C106DD]DJ-1 non-covalently bound to ASK1 even in the absence of hydrogen peroxide and conferred partial cytoprotection. Interestingly, mutations of peripheral redox sites (C46A and C53A) and M26I also led to constitutive ASK1 binding. Cytoprotective [wt]DJ-1 bound to the ASK1 N terminus (which is known to bind another negative regulator, thioredoxin 1), whereas [M26I]DJ-1 bound to aberrant C-terminal site(s). Consequently, the peripheral cysteine mutants retained cytoprotective activity, whereas the PD-associated mutant [M26I]DJ-1 failed to suppress ASK1 activity and nuclear export of the death domain-associated protein Daxx and did not promote cytoprotection. Thus, cytoprotective binding of DJ-1 to ASK1 depends on the central redox-sensitive Cys-106 and may be modulated by peripheral cysteine residues. We suggest that impairments in oxidative conformation changes of DJ-1 might contribute to PD neurodegeneration.
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PMID:Oxidizable residues mediating protein stability and cytoprotective interaction of DJ-1 with apoptosis signal-regulating kinase 1. 1929 55

Several studies have shown that catecholamines can inhibit the fibrillation of alpha-synuclein (alpha-Syn), a small presynaptic protein whose aggregation is believed to be a critical step in the etiology of Parkinson's disease and several other neurodegenerative disorders. However, the mechanism of this inhibition is uncertain. We show here that substoichiometric concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a normal product of the metabolism of dopamine, can inhibit the fibrillation of alpha-Syn, due to non-covalent binding of DOPAC to alpha-Syn monomer. Intriguingly, the presence of alpha-Syn accelerates the spontaneous oxidation of DOPAC, and the oxidized form of DOPAC (the quinone) is responsible for the fibrillation inhibition. In addition, the presence of DOPAC leads to the oxidation of the methionine residues of alpha-Syn, probably due to the H(2)O(2) production as a by-product of DOPAC oxidation. The lack of fibrillation results from the formation of stable oligomers, which are very similar to those observed transiently at early stages of the alpha-Syn fibrillation. A possible explanation for this phenomenon is that DOPAC stabilizes the normally transient oligomers and prevents them from subsequent fibril formation. The analysis of the alpha-Syn Y39W variant suggests that DOPAC binds non-covalently to the same N-terminal region of alpha-Syn as lipid vesicles, probably in the vicinity of residue 39. In contrast to the compounds with 1,2-dihydroxyphenyl groups (DOPAC and catechol), their 1,4-dihydroxyphenyl isomers (hydroquinone and homogentisic acid) are able to modify alpha-Syn covalently, probably due to the less steric hindrance in the Michael addition.
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PMID:At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to alpha-synuclein and prevents its fibrillation. 1932 9

Markers of oxidative stress were measured in blood samples of 338 subjects (965 observations): Alzheimer's, vascular dementia, diabetes (type II) superimposed to dementias, Parkinson's disease and controls. Patients showed increased thiobarbituric acid reactive substances (+21%; P < 0.05), copper-zinc superoxide dismutase (+64%; P < 0.001) and decreased antioxidant capacity (-28%; P < 0.001); pairs of variables resulted linearly related across groups (P < 0.001). Catalase and glutathione peroxidase, involved in discrimination between diseases, resulted non-significant. When diabetes is superimposed with dementias, changes resulted less marked but significant. Also, superoxide dismutase resulted not linearly correlated with any other variable or age-related (pure Alzheimer's peaks at 70 years, P < 0.001). Systemic oxidative stress was significantly associated (P << 0.001) with all diseases indicating a disbalance in peripheral/adaptive responses to oxidative disorders through different free radical metabolic pathways. While other changes - methionine cycle, insulin correlation - are also associated with dementias, the responses presented here show a simple linear relation between prooxidants and antioxidant defenses.
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PMID:Systemic oxidative stress associated with the neurological diseases of aging. 1948 52

Aggregated alpha-synuclein and the point mutations Ala30Pro and Ala53Thr of alpha-synuclein are associated with Parkinson's disease. The physiological roles of alpha-synuclein and methionine oxidation of the alpha-synuclein protein structure and function are not fully understood. Methionine sulfoxide reductase A (MsrA) reduces methionine sulfoxide residues and functions as an antioxidant. To monitor the effect of methionine oxidation to alpha-synuclein on basic cellular processes, alpha-synucleins were expressed in msrA null mutant and wild-type yeast cells. Protein degradation was inhibited in the alpha-synuclein-expressing msrA null mutant cells compared to alpha-synuclein-expressing wild-type cells. Increased inhibition of degradation and elevated accumulations of fibrillated proteins were observed in SynA30P-expressing msrA null mutant cells. Additionally, methionine oxidation inhibited alpha-synuclein phosphorylation in yeast cells and in vitro by casein kinase 2. Thus, a compromised MsrA function combined with alpha-synuclein overexpression may promote processes leading to synucleinopathies.
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PMID:Clearance and phosphorylation of alpha-synuclein are inhibited in methionine sulfoxide reductase a null yeast cells. 1965 31

Cognitive abnormalities are common in Parkinson's disease, with important social and economic implications. Factors influencing their evolution remain unclear but are crucial to the development of targeted therapeutic strategies. We have investigated the development of cognitive impairment and dementia in Parkinson's disease using a longitudinal approach in a population-representative incident cohort (CamPaIGN study, n = 126) and here present the 5-year follow-up data from this study. Our previous work has implicated two genetic factors in the development of cognitive dysfunction in Parkinson's disease, namely the genes for catechol-O-methyltransferase (COMT Val(158)Met) and microtubule-associated protein tau (MAPT) H1/H2. Here, we have explored the influence of these genes in our incident cohort and an additional cross-sectional prevalent cohort (n = 386), and investigated the effect of MAPT H1/H2 haplotypes on tau transcription in post-mortem brain samples from patients with Lewy body disease and controls. Seventeen percent of incident patients developed dementia over 5 years [incidence 38.7 (23.9-59.3) per 1000 person-years]. We have demonstrated that three baseline measures, namely, age >or=72 years, semantic fluency less than 20 words in 90 s and inability to copy an intersecting pentagons figure, are significant predictors of dementia risk, thus validating our previous findings. In combination, these factors had an odds ratio of 88 for dementia within the first 5 years from diagnosis and may reflect the syndrome of mild cognitive impairment of Parkinson's disease. Phonemic fluency and other frontally based tasks were not associated with dementia risk. MAPT H1/H1 genotype was an independent predictor of dementia risk (odds ratio = 12.1) and the H1 versus H2 haplotype was associated with a 20% increase in transcription of 4-repeat tau in Lewy body disease brains. In contrast, COMT genotype had no effect on dementia, but a significant impact on Tower of London performance, a frontostriatally based executive task, which was dynamic, such that the ability to solve this task changed with disease progression. Hence, we have identified three highly informative predictors of dementia in Parkinson's disease, which can be easily translated into the clinic, and established that MAPT H1/H1 genotype is an important risk factor with functional effects on tau transcription. Our work suggests that the dementing process in Parkinson's disease is predictable and related to tau while frontal-executive dysfunction evolves independently with a more dopaminergic basis and better prognosis.
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PMID:The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. 1981 13

We investigated epidemiologic data from 61 cases of autopsy-confirmed sporadic Creutzfeldt-Jakob disease (CJD). Dura mater-associated CJD cases and familial CJD cases were excluded. There were 34 male and 27 female cases, with an average age at onset of 66.0 +/- 10.5 years (range 27 to 89). At onset of CJD, 1 case was aged in the 20's and 1 in 30's, but there were no cases aged in the 40's. In 6 cases, age at onset was in the 80's. There was no significant difference in relation to the age at onset between males and females, averaging 66.2 +/- 12.4 years (range 27 to 89), and 65.9 7.5 years (range 53 to 82), respectively. Two cases had been employed as medical workers (a medical technologist and a nurses' aide) but neither had an apparent history of contact with CJD patients. No cases in the study had either family history of CJD or apparent contact with CJD patients. Ten cases had a history of hypertension, 5 cases had a history of diabetes mellitus, 2 cases had a history of malaria and 1 case had suffered from atomic bomb exposure. Twenty-one cases had operation history, including 2 cases of an operation involving the central nervous system. One case had a skull-base fracture operation 19 years before the onset of CJD and the other case had an atlantoaxial subluxation operation 11 years before the onset of CJD; there was no transplantation of dura mater graft in either operation. There was one case with a history of conservative treatment for cerebral hemorrhage; this case had symptomatic secondary epilepsy as a coexisting disease at the onset of CJD. Two cases had Parkinson's disease as a coexisting disease at the onset of CJD. The source hospitals enforcing medical treatment were located in the Aichi (n = 42), Gifu (n = 12) and Mie (n = 7) prefectures of the Tokai region of Japan. Regarding patients' place of residence, 22 cases resided in Nagoya-city. Nagoya University Hospital performed the autopsy in 12 cases, but 10 cases of those were transported after death from the source hospital. Departments of neurology provided clinical treatment in 54 cases. Other departments that provided treatment were Internal Medicine (n = 3), Psychiatry (n = 2), Geriatrics (n = 1), and Neurosurgery (n = 1). In 39 cases, prion protein gene analyses using peripheral blood leukocyte or cryopreserved brain tissue were performed. As for polymorphic codon 129, 36 cases (92%) showed Met/Met, 3 cases showed Met/Val (8%) and no case showed Val/Val polymorphism. Polymorphic codon 219 showed Glu/Glu homozygosity in all of the examined cases. Active autopsy performance of CJD in the Tokai region was suggested from the present study. We estimated that the CJD autopsy rate of the district was more than 50% over the past 7 years.
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PMID:[Epidemiologic study of Creutzfeldt-Jakob disease from autopsy-confirmed cases]. 1982 94


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