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)

Studies have shown that alpha-synuclein (alpha-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) alpha-syn and two human alpha-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant alpha-syn expressed on the injected side was about four times the endogenous rat alpha-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt alpha-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates alpha-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates alpha-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.
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PMID:The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease. 1817 17

Of all the molecules reported to have toxicological effects, BMAA (beta-methylamino alanine) stands out as having the most checkered past. In the late 1960's it was reported to be a toxic component of the cycad flour consumed by Chamorros on Guam which caused the high incidence of amyotrophic lateral sclerosis (ALS) in Guam, that was associated with a Parkinson's disease-like dementia complex (ALS-PDC). However, because ALS-PDC is a slow onset disease, manifesting itself as long as 30 years following exposure to the putative neurotoxin, and only acute toxic effects of BMAA were observed in animal studies, interest in BMAA waned. A seminal study by Spencer et al., in 1987 showing neurological impairments with long-term BMAA-fed monkeys revived the hypothesis that BMAA could cause ALS-PDC. However, the amounts of BMAA used in that study were viewed as being the equivalent of a person consuming their body weight of cycad flour every day. Again, the BMAA hypothesis was discarded. Recently a third iteration of the BMAA hypothesis has been proposed. It is based on the discovery of a novel dietary source of BMAA via biomagnification of BMAA in flying foxes, once consumed in great amounts by Chamorros. Also, reports that BMAA can be incorporated into plant and animal proteins, a heretofore unrecognized dietary source of BMAA, further solidified this new hypothesis. However, once again this hypothesis has its detractors and it remains controversial. This manuscript critically evaluates in vivo studies directed at establishing an animal model of BMAA-induced ALS-PDC and their implications for this hypothesis.
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PMID:Animal models of BMAA neurotoxicity: a critical review. 1819 17

The aggregation of alpha-synuclein, a presynaptic protein, has an important role in the etiology of Parkinson's disease. Oligomers or protofibrils adopting the cross-beta-sheet structure characteristic of fibrillating amyloid proteins are presumed to be the primary cytotoxic species. Current techniques for monitoring the kinetics of alpha-synuclein aggregation based on fluorescent dyes such as Thioflavin-T and Congo red detect only the terminal fibrillar species, are discontinuous and notoriously irreproducible. We have devised a new fluorescence aggregation assay that is continuous and provides a large set of fluorescence parameters sensitive to the presence of oligomeric intermediates as well as fibrils. The approach involves tagging functionally neutral Ala-to-Cys variants of alpha-synuclein with the long-lifetime fluorophore pyrene. Upon induction of aggregation at 37 degrees C, the entire family of steady-state descriptors of pyrene emission (monomer intensity, solvent polarity ratio (I(I)/I(III)), and anisotropy; and excimer intensity) change dramatically, particularly during the early stages in which oligomeric intermediates form and evolve. The pyrene probe senses a progressive decrease in polarity, an increase in molecular mass and close intermolecular association in a manner dependent on position in the sequence and the presence of point mutations. The time-resolved decays (0-160 ns) of intensity and anisotropy exhibited complex, characteristic features. The new assay constitutes a convenient platform for the high-throughput screening of agents useful in the diagnosis and therapy of Parkinson's disease as well as in basic investigations.
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PMID:Multiparametric fluorescence detection of early stages in the amyloid protein aggregation of pyrene-labeled alpha-synuclein. 1843 72

In the mountains of Peru, globular colonies of Nostoc commune (Nostocales) are collected in the highland lakes by the indigenous people, who call them llullucha. They are consumed locally, traded for maize, or sold, eventually entering the folk markets of Cusco and other neighboring cities. Throughout highland Peru, Nostoc commune is highly salient as a seasonal dietary item, being eaten alone, or in picante -- a local stew -- and is said to be highly nutritious. Nostoc commune has been known to produce unusual amino acids, including those of the mycosporine group, which possibly function to prevent UV damage. We analyzed 21 different Nostoc commune spherical colonies from 7 different market collections in the Cusco area for the presence of beta-N-methylamino-L-alanine (BMAA), a neurotoxic amino acid produced by diverse taxa of cyanobacteria, using four different analytical techniques (HPLC-FD, UPLC-UV, UPLC/MS, LC/MS/MS). We found using all four techniques that BMAA was present in the samples purchased in the Peruvian markets. Since BMAA has been putatively linked to neurodegenerative illness, it would be of interest to know if the occurrence of ALS, Alzheimer's, or Parkinson's Disease is greater among individuals who consume llullucha in Peru.
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PMID:Cyanobacteria (Nostoc commune) used as a dietary item in the Peruvian highlands produce the neurotoxic amino acid BMAA. 1849 96

Substantial evidence suggests that the fibrillation of alpha-synuclein is a critical step in the development of Parkinson's disease. In vitro, alpha-synuclein forms fibrils with morphologies and a staining characteristic similar to those extracted from disease-affected brain. Monomeric alpha-synuclein is an intrinsically disordered protein, with three Tyr residues in the C-terminal region, one in the N-terminus, and lacking Trp. It is thought that interactions between the C-terminus and the central portion of the molecule may prevent or minimize aggregation/fibrillation. To test this hypothesis we examined the importance of the Tyr residues on the propensity for alpha-synuclein to fibrillate in vitro. Fibril formation of alpha-synuclein was completely inhibited, in the timescale over which measurements were made, by replacing the three C-terminal Tyr residues with Ala. In addition, substitution of Tyr133 by Ala also resulted in the absence of fibrillation, whereas the individual Y125A and Y136A mutants showed limited inhibition. Replacement of Tyr39 by Ala also resulted in substantial inhibition of fibrillation. Structural analysis showed that the Y133A mutant had a substantially different conformation, rich in alpha-helical secondary structure, as compared with the wild-type and other mutants, although the formation of any tertiary structure has not been observed as can be judged from near-UV-CD spectra. These observations suggest that the long-range intramolecular interactions between the N- and C-termini of alpha-synuclein are likely to be crucial to the fibrillation process.
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PMID:Impact of Tyr to Ala mutations on alpha-synuclein fibrillation and structural properties. 1869 32

Safety and efficacy of tolcapone was studied in 237 patients with advanced Parkinson's disease (PD) in a prospective, open-label, multicenter, non-interventional trial. Main outcome measures were tolerability (adverse events=AE) and safety parameters (liver enzymes). A subgroup analysis was performed for patients at < 70 years and > or = 70 years of age. Improvement of symptoms based on investigator global assessment was reported in 84% of all patients: 14.8% greatly improved, 42.6% improved, and 27% slightly improved. Slight worsening was reported in only 2.6% of subjects. There were no significant differences concerning the treatment efficacy between the age subgroups (p=0.74). The incidence of AE was slightly higher in the subgroup of patients > or = 70 years than in the subgroup of patients < 70 years (relative risk, RR=3.03; 95% confidence interval, CI=1.04-8.96; p=0.03), but AE judged as potentially related to tolcapone were equally distributed among both groups (8.5% vs. 2.9%, RR: 2.91; CI=0.82-10.27; p=0.08). Diarrhea was the most common potentially tolcapone-related AE in both groups. Elevations of liver enzymes (aspartate aminotransferase=AST, and alanine aminotransferase=ALT) above the upper limit of normal were observed in 19% (CI=8.3-23.4) of all patients with slightly but not statistically significant higher percentages in the young patients group compared to older patient group (RR=0.54; CI=0.28-1.04; p=0.06). This observational study provides evidence that tolcapone can be effectively and safely used for the treatment of response fluctuations in elderly patients with PD.
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PMID:Tolcapone in elderly patients with Parkinson's disease: a prospective open-label multicenter non-interventional trial. 1883 49

The interplay between dopamine and alpha-synuclein (AS) plays a central role in Parkinson's disease (PD). PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD) simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the (125)YEMPS(129) region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83) in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the (125)YEMPS(129) region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A) abolishes the ability of dopamine to inhibit AS fibrillization.
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PMID:Inhibition of alpha-synuclein fibrillization by dopamine is mediated by interactions with five C-terminal residues and with E83 in the NAC region. 1885 92

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

Alpha-synuclein (alpha-syn), a protein implicated in Parkinson's disease, is structurally diverse. In addition to its random-coil state, alpha-syn can adopt an alpha-helical structure upon lipid membrane binding or a beta-sheet structure upon aggregation. We used yeast biology and in vitro biochemistry to detect how sequence changes alter the structural propensity of alpha-syn. The N-terminus of the protein, which adopts an alpha-helical conformation upon lipid binding, is essential for membrane binding in yeast, and variants that are more prone to forming an alpha-helical structure in vitro are generally more toxic to yeast. beta-Sheet structure and inclusion formation, on the other hand, appear to be protective, possibly by sequestering the protein from the membrane. Surprisingly, sequential deletion of residues 2 through 11 caused a dramatic drop in alpha-helical propensity, vesicle binding in vitro, and membrane binding and toxicity in yeast, part of which could be mimicked by mutating aspartic acid at position 2 to alanine. Variants with distinct structural preferences, identified here by a reductionist approach, provide valuable tools for elucidating the nature of toxic forms of alpha-syn in neurons.
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PMID:The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast. 1928 89

Convergent evidence indicates that in later stages of Parkinson's disease raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine neurons by converting and releasing dopamine derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine (L-dopa). Because the serotonin system is not equipped with dopamine autoregulatory mechanisms, it has been postulated that raphe-mediated striatal dopamine release may fluctuate dramatically. These fluctuations may portend the development of abnormal involuntary movements called L-dopa-induced dyskinesia (LID). As such, it has been hypothesized that reducing the activity of raphestriatal neurons could dampen supraphysiological stimulation of striatal dopamine receptors thereby alleviating LID. To directly address this, the current study employed the rodent model of LID to investigate the contribution of the rostral raphe nuclei (RRN) in the development, expression and treatment of LID. In the first study, dual serotonin/dopamine selective lesions of the RRN and medial forebrain bundle, respectively, verified that the RRN are essential for the development of LID. In a direct investigation into the neuroanatomical specificity of these effects, microinfusions of +/-8-OH-DPAT into the intact dorsal raphe nucleus dose-dependently attenuated the expression of LID without affecting the antiparkinsonian efficacy of L-dopa. These current findings reveal the integral contribution of the RRN in the development and expression of LID and implicate a prominent role for dorsal raphe 5-HT1AR in the efficacious properties of 5-HT1AR agonists.
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PMID:The role of the dorsal raphe nucleus in the development, expression, and treatment of L-dopa-induced dyskinesia in hemiparkinsonian rats. 1930 58


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