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)

Alpha-synuclein (alpha-syn) is the major protein component of the insoluble fibrils that make up Lewy bodies, the hallmark lesions of Parkinson's disease. Its C-terminal region contains motifs of charged amino acids that potentially bind metal ions, as well as several identified phosphorylation sites. We have investigated the metal-binding properties of synthetic model peptides and phosphopeptides that correspond to residues 119-132 of the C-terminal, polyacidic stretch of human alpha-syn, with the sequence Ac-Asp-Pro-Asp-Asn-Glu-Ala-Tyr-Glu-Met-Pro-Ser-Glu-Glu-Gly (alpha-syn119-132). The peptide pY125 replaces tyrosine with phosphotyrosine, whereas pS129 replaces serine with phosphoserine. By using Tb(3+) as a luminescent probe of metal binding, we find a marked selectivity of pY125 for Tb(3+) compared with pS129 and alpha-syn119-132, a result confirmed by isothermal titration calorimetry. Truncated or alanine-substituted peptides show that the phosphoester group on tyrosine provides a metal-binding anchor that is supplemented by carboxylic acid groups at positions 119, 121, and 126 to establish a multidentate ligand, while two glutamic acid residues at positions 130 and 131 contribute to binding additional Tb(3+) ions. The interaction of other metal ions was investigated by electrospray ionization mass spectrometry, which confirmed that pY125 is selective for trivalent metal ions over divalent metal ions, and revealed that Fe(3+) and Al(3+) induce peptide dimerization through metal ion cross-links. Circular dichroism showed that Fe(3+) can induce a partially folded structure for pY125, whereas no change was observed for pS129 or the unphosphorylated analog. The results of this study show that the type and location of a phosphorylated amino acid influence a peptide's metal-binding specificity and affinity as well as its overall conformation.
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PMID:Phosphorylation-dependent metal binding by alpha-synuclein peptide fragments. 1708 19

Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.
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PMID:Homocysteine and Parkinson's disease: a dangerous liaison? 1733 37

Cognitive dysfunction commonly occurs even in the early stages of Parkinson's disease (PD). Impairment on frontostriatally based executive tasks is particularly well described but affects only a proportion of early PD patients. Our previous work suggests that a common functional polymorphism (val(158)met) within the catechol O-methyltransferase (COMT) gene underlies some of this executive heterogeneity. In particular, an increasing number of methionine alleles, resulting in lower enzyme activity, is associated with impaired performance on the "Tower of London" planning task. The main objective of this study was to investigate the underlying neural basis of this genotype-phenotype effect in PD using functional magnetic resonance imaging. We scanned 31 patients with early PD who were homozygous for either valine (val) (n = 16) or methionine (met) (n = 15) at the COMT val(158)met polymorphism during performance of an executive task comprising both Tower of London (planning) and simple subtracting ("control") problems. A cross-group comparison between genetic subgroups revealed that response times for planning problems were significantly longer in met compared with val homozygotes, whereas response times for control problems did not differ. Furthermore, imaging data revealed a significant reduction in blood oxygen level-dependent signal across the frontoparietal network involved in planning in met/met compared with val/val patients. Hence, we have demonstrated that COMT genotype impacts on executive function in PD through directly influencing frontoparietal activation. Furthermore, the directionality of the genotype-phenotype effect observed in this study, when interpreted in the context of the existing literature, adds weight to the hypothesis that the relationship between prefrontal function and dopamine levels follows as an inverted U-shaped curve.
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PMID:Catechol O-methyltransferase Val158Met genotype influences frontoparietal activity during planning in patients with Parkinson's disease. 1747 91

Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha-synuclein inclusions in a sporadic, methioninelvaline type 1, Creutzfeldt-Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha-synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson's disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient's age (79 years at autopsy) and the over 2-year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha-synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology-based surveillance systems.
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PMID:A sporadic case of Creutzfeldt-Jakob disease with beta-amyloid deposits and alpha-synuclein inclusions. 1764 42

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are accompanied by increased levels of 8-oxo-2'-deoxyguanosine (8-oxo2dG) and alterations in levels of homocysteine (Hcy), methionine (Met), and cysteine (Cys). Hcy may undergo remethylation due to involvement of MTHFR, MTR and MTHFD1 proteins. Present studies are aimed at determination of 8-oxo2dG, Hcy, Met, and Cys in AD and PD patients as well as in control groups, using HPLC/EC/UV, as well as estimation, by restriction analysis, frequency of following gene polymorphisms: MTHFR (C677T, A1298C, G1793A), MTHFD1 (G1958A), and MTR (A2756G). In AD there were significant differences of the levels of only Cys (GG, MTHFR, G1793A) and Met/Hcy (AA, MTHFD1, G1958A) whereas in PD there were more significant differences of the levels of thiols: Hcy [MTHFR: CT (C677T) and GG (G1793A); MTR, AG (A2756G)], Met [MTR, AA (A2756G)], Cys [MTR, AG (A2756G)], and Met/Hcy [MTHFR: CC, CT (C677T) and AA (A1298C), and GG (G1793A); MTHFD1 AA(G1958A); MTR AA(A2756G)]. Significant differences in the levels of Cys/Hcy, MTHFD1 GA (G1958) were varied between AD and PD groups. The results indicate that of the enzymes studied only polymorphisms of folate-dependent enzyme MTHFD1 have pointed to significant differences in intensity of turnover of circulating thiols between AD and PD patients.
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PMID:Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. 1769 Dec 19

Folate and vitamin B(12) are essential cofactors for the methionine/homocysteine cycle in the brain. These vitamins mediate the remethylation of homocysteine (Hcy), which affects the production of the universal methyl donor, S-adenosylmethionine (SAM), in the brain among other organs. Additionally, increased plasma concentrations of total Hcy (tHcy) are associated with cerebrovascular disease and can compromise the blood-brain barrier. tHcy concentrations in the brain and cerebrospinal fluid become increased in several psychiatric and neurological disorders. Disturbances in the transmethylation pathway indicated by abnormal SAM, S-adenosylhomocysteine or their ratio have been reported in many neurodegenerative diseases, such as dementia, depression or Parkinson's disease. Cobalamin is essential for neuronal generation and its deficiency can cause degeneration of the nervous system. Available data emphasize that deficiency of folate and vitamin B(12) can lead to elevated concentrations of tHcy and disturbed methylation potential in the brain. Therefore, acquired or inherited disorders in these metabolic pathways are associated with brain abnormalities and severe neurological symptoms that are mostly irreversible, even after providing the missing cofactors. This review discusses the relationship between brain and blood levels of key vitamins and metabolites related to one carbon metabolism.
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PMID:Biomarkers of folate and vitamin B(12) status in cerebrospinal fluid. 1789 39

The purpose of this study was to investigate associations between recreational physical activity and Parkinson's disease (PD) risk. We prospectively followed 143,325 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2001 (mean age at baseline = 63). Recreational physical activity was estimated at baseline from the reported number of hours per week on average spent performing light intensity activities (walking, dancing) and moderate to vigorous intensity activities (jogging/running, lap swimming, tennis/racquetball, bicycling/stationary bike, aerobics/calisthenics). Incident cases of PD (n = 413) were confirmed by treating physicians and medical record review. Relative risks (RR) were estimated using proportional hazards models, adjusting for age, gender, smoking, and other risk factors. Risk of PD declined in the highest categories of baseline recreational activity. The RR comparing the highest category of total recreational activity (men > or = 23 metabolic equivalent task-hours/week [MET-h/wk], women > or = 18.5 MET-h/wk) to no activity was 0.8 (95% CI: 0.6, 1.2; P trend = 0.07). When light activity and moderate to vigorous activity were examined separately, only the latter was found to be associated with PD risk. The RR comparing the highest category of moderate to vigorous activity (men > or = 16 MET-h/wk, women > or = 11.5 MET-h/wk) to the lowest (0 MET-h/wk) was 0.6 (95% CI: 0.4, 1.0; P trend = 0.02). These results did not differ significantly by gender. The results were similar when we excluded cases with symptom onset in the first 4 years of follow-up. Our results may be explained either by a reduction in PD risk through moderate to vigorous activity, or by decreased baseline recreational activity due to preclinical PD.
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PMID:Recreational physical activity and risk of Parkinson's disease. 1796 Aug 18

Parkinson's disease (PD), a common neurodegenerative disease, is caused by loss of dopaminergic neurons in the substantia nigra. Although the underlying cause of the neuronal loss is unknown, oxidative stress is thought to play a major role in the pathogenesis of PD. The amino acid methionine is readily oxidized to methionine sulfoxide, and its reduction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs). The reversible oxidation-reduction cycle of methionine involving MSRs has been postulated to act as a catalytic antioxidant system protecting cells from oxidative damage. Here, we show that one member of the MSR family, MSRA, inhibits development of the locomotor and circadian rhythm defects caused by ectopic expression of human alpha-synuclein in the Drosophila nervous system. Furthermore, we demonstrate that one way to enhance the MSRA antioxidant system is dietary supplementation with S-methyl-L-cysteine (SMLC), found abundantly in garlic, cabbage, and turnips. SMLC, a substrate in the catalytic antioxidant system mediated by MSRA, prevents the alpha-synuclein-induced abnormalities. Therefore, interventions focusing on the enzymatic reduction of oxidized methionine catalyzed by MSRA represent a new prevention and therapeutic approach for PD and potentially for other neurodegenerative diseases involving oxidative stress.
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PMID:Methionine sulfoxide reductase A and a dietary supplement S-methyl-L-cysteine prevent Parkinson's-like symptoms. 1803 52

Substance P is an important neurotransmitter or neuromodulator in central nervous system. Morphological studies have revealed the existence of substance P and its high affinity receptor, neurokinin-1 receptor, in globus pallidus. The expression of neurokinin-1 receptor in external globus pallidus has been reported to be decreased or unchanged in parkinsonian patients. To further investigate the effects of pallidal neurokinin-1 receptor in Parkinson's disease, an in vivo extracellular recording in 6-hydroxydopamine parkinsonian rats was performed. Micro-pressure ejection of selective neurokinin-1 receptor agonist, [Sar9,Met(O2)11] substance P (0.1mM), increased the spontaneous firing rate of pallidal neurons by 9.1% on the lesioned side, which was significantly weaker than that on the unlesioned side (20.7%), and that in normal rats (30.0%). The selective neurokinin-1 receptor antagonist, SR140333B, prevented the excitatory effects induced by [Sar9,Met(O2)11] substance P. Based on the action of substance P in globus pallidus of parkinsonian rats we hypothesize that the activity of neurokinin-1 receptors in globus pallidus may be decreased under parkinsonian state. This finding may provide a rationale for further investigations into the potential of pallidal substance P system in the treatment of Parkinson's disease.
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PMID:Effects of substance P on neuronal firing of pallidal neurons in parkinsonian rats. 1805 2

Polymorphism in prion protein (PrP) is related to different phenotypes of spongiform encephalopathies and some mental illnesses. The octarepeat region of PrP, encompassing the codon 51 through 91, is related to cellular anti-oxidation function and may play a role in genetic contribution of PrP polymorphism to neurodegeneration, such as Parkinson's disease (PD). We analyzed the genomic patterns of PrP gene from 528 subjects and found a predominance of Met/Met variant at codon 129 of PD subjects without significant difference (97.3%, and 96.5% in controls). But among PD subjects there were one with heterozygosity of silent nucleotide substitution (NS) on octarepeats (R1-2-3g-3-4/R1-2-2-3-4) and three with heterozygosity of single copy deletion (CD) on octarepeats (R1-2-3-4/R1-2-2-3-4). Consistent genomic DNA and cDNA sequences were found in a PD subject without any octarepeat changes and the one with NS, but R1-2-3g-3-4/R1-2-2-3-4 of cDNA pattern occurred in the one with genomic CD. This is the first report of the polymorphic PrP octarepeat change among those with parkinsonism. We proposed a hypothesis about an initial secondary hairpin structure of the template strand followed by the transcript "shift backward" due to the high homology of the sequences between R2 and R3 motifs while synthesizing RNA. This phenomenon may be a key step of neurodegeneration resulting from PrP polymorphism and require further studies.
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PMID:Octarepeat changes of prion protein in Parkinson's disease. 1845 51


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