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 is a pathological component of Parkinson's disease by constituting the filamentous component of Lewy bodies. Phthalocyanine (Pc) effects on the amyloidosis of alpha-synuclein have been examined. The copper complex of phthalocyanine tetrasulfonate (PcTS-Cu(2+)) caused the self-oligomerization of alpha-synuclein while Pc-Cu(2+) did not affect the protein, indicating that introduction of the sulfonate groups was critical for the selective protein interaction. The PcTS-Cu(2+) interaction with alpha-synuclein has occurred predominantly at the N-terminal region of the protein with a K(d) of 0.83 microM apart from the hydrophobic NAC (non-Abeta component of Alzheimer's disease amyloid) segment. Phthalocyanine tetrasulfonate (PcTS) lacking the intercalated copper ion also showed a considerable affinity toward alpha-synuclein with a K(d) of 3.12 microM, and its binding site, on the other hand, was located at the acidic C-terminus. These mutually exclusive interactions between PcTS and PcTS-Cu(2+) toward alpha-synuclein resulted in distinctive features on the kinetics of protein aggregation, morphologies of the final aggregates, and their in vitro cytotoxicities. The PcTS actually suppressed the fibrous amyloid formation of alpha-synuclein, but it produced the chopped-wood-looking protein aggregates. The aggregates showed rather low toxicity (9.5%) on human neuroblastoma cells (SH-SY5Y). In fact, the PcTS was shown to effectively rescue the cell death of alpha-synuclein overexpressing cells caused by the lactacystin treatment as a proteasome inhibitor. The anti-aggregative and anti-amyloidogenic properties of PcTS were also demonstrated with alcohol dehydrogenase, glutathione S-transferase, and amyloid beta/A4 protein under their aggregative conditions. The PcTS-Cu(2+), on the other hand, promoted the protein aggregation of alpha-synuclein, which gave rise to the fibrillar protein aggregates whose cytotoxicity became significant to 35.8%. Taken together, the data provided in this study indicate that PcTS/PcTS-Cu(2+) could be considered as possible candidates for the development of therapeutic or prophylactic strategies against the alpha-synuclein-related neurodegenerative disorders.
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PMID:Phthalocyanine tetrasulfonates affect the amyloid formation and cytotoxicity of alpha-synuclein. 1503 41

Protein aggregation is a notable feature of various human disorders, including Parkinson's disease, Alzheimer's disease and many others systemic amyloidoses. An increasing number of observations in vitro suggest that transition metals are able to accelerate the aggregation process of several proteins found in pathological deposits, e.g. alpha-synuclein, amyloid beta (Abeta) peptide, beta(2)-microglobulin and fragments of the prion protein. Here we report the effects of metal ions on the aggregation rate of human muscle acylphosphatase, a suitable model system for aggregation studies in vitro. Among the different species tested, Cu(2+) produced the most remarkable acceleration of aggregation, the rate of the process being 2.5-fold higher in the presence of 0.1 mM metal concentration. Data reported in the literature suggest the possible role played by histidine residues or negatively charged clusters present in the amino acid sequence in Cu(2+)-mediated aggregation of pathological proteins. Acylphosphatase does not contain histidine residues and is a basic protein. A number of histidine-containing mutational variants of acylphosphatase were produced to evaluate the importance of histidine in the aggregation process. The Cu(2+)-induced acceleration of aggregation was not significantly altered in the protein variants. The different aggregation rates shown by each variant were entirely explained by the changes of hydrophobicity or propensity to form a beta structure introduced by the point mutation. The effect of Cu(2+) on acylphosphatase aggregation cannot therefore be attributed to the specific factors usually invoked in the aggregation of pathological proteins. The effect, rather, seems to be a general related to the chemistry of the polypeptide backbone and could represent an additional deleterious factor resulting from the alteration of the homeostasis of metal ions in cells.
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PMID:Investigation of the effects of copper ions on protein aggregation using a model system. 1509 18

Membrane lipid peroxidation and oxidative modification of various membrane and associated proteins (e.g., receptors, ion transporters and channels, and signal transduction and cytoskeletal proteins) occur in a range of neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably iron and copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific neurological disorders are being elucidated. In Alzheimer's disease (AD), the amyloid beta-peptide generates reactive oxygen species and induces MAOS, resulting in disruption of cellular calcium homeostasis. In Parkinson's disease (PD), mitochondrial toxins and perturbed ubiquitin-dependent proteolysis may impair ATP production and increase oxyradical production and MAOS. The inheritance of polyglutamine-expanded huntingtin may promote neuronal degeneration in Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g., Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of iron and copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.
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PMID:Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders. 1510 54

Inflammation-mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with antiinflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque-developing mice with amyloid beta peptide (Abeta) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neurodegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets.
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PMID:Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. 1595 56

Alpha-synuclein is a major component of several pathological lesions diagnostic of specific neurodegenerative disease such as Parkinson's disease. This study focuses on the non-amyloid beta component of Alzheimer's disease amyloid, a key region for the aggregation and fibril formation of alpha-synuclein. Several mutations were introduced in an attempt to repress beta-strand formation and hydrophobic interaction-based aggregation. Although reducing the hydrophobicity drastically decreased fibril formation, the Val70Thr and Val70Pro mutations resulted in an unstable secondary structure thereby increasing non-structural aggregation, instead of fibril formation. Therefore, the stabilization of non-structural natively unfolded status is important to prevent alpha-synuclein fibril formation. Mixing the Val70Thr/Val71Thr double mutant, which has inherently low potential, with the fibril forming alpha-synucleins, WT and Ala53Thr, greatly reduced their fibril formation and aggregation. This double mutant has great potential for further therapeutic approaches.
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PMID:Engineered alpha-synuclein prevents wild type and familial Parkin variant fibril formation. 1608 Oct 40

Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the destabilization of preformed fAbeta in the central nervous system would be attractive therapeutic targets for the treatment of Alzheimer's disease (AD). Many studies have demonstrated that oxidative damage plays a central role in AD pathogenesis, as well as Parkinson disease (PD). Among the antioxidant strategies proposed, increasing evidence points to the possibility of achieving neuroprotection by dopamine agonists, as well as monoamine oxidase B (MAO-B) inhibitors. Actually, the beneficial effect of selegiline, a MAO-B inhibitor, in AD has been noted in several clinical studies. On the reverse, antimuscarinic agents have been reported to accelerate beta-amyloidosis and senile plaque formation in PD. Using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, we examined the effects of anti-Parkinsonian agents, dopamine, levodopa, pergolide, bromocriptine, selegiline, and trihexyphenidyl on the formation, extension, and destabilization of fAbeta(1-40) and fAbeta(1-42) at pH 7.5 at 37 degrees C in vitro. The anti-Parkinsonian agents other than trihexyphenidyl dose-dependently inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42), as well as their extension. Moreover, these agents dose-dependently destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: dopamine>selegiline>levodopa=pergolide>bromocriptine. Although the exact mechanism of the anti-amyloidogenic activity of these agents is unclear, these and other structurally related compounds could be key molecules for the development of therapeutics for AD and other conformational diseases.
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PMID:Anti-Parkinsonian agents have anti-amyloidogenic activity for Alzheimer's beta-amyloid fibrils in vitro. 1634 94

Alpha-synuclein (ASN), a 140-amino acid protein, is richly expressed in presynaptic terminals in the central nervous system, where it plays a role in synaptic vesicle function. However, if it is altered and accumulated it is involved in neurodegeneration as Parkinson's disease (PD). ASN contained 35-amino acid domain known as non-amyloid beta component of Alzheimer's disease amyloid (NAC) that is probably responsible for its aggregation and toxicity. Up till now the role of ASN in dopaminergic system function and in pathogenesis of PD is unknown. The aim of this study was to determine the effect of brain aging and the role of ASN and NAC peptide on striatal dopamine transporter (DAT) function. The study was carried out using radiochemical and spectrofluorimetrical determination. It was found that DAT activity assessed by measuring [3H]-dopamine (DA) uptake into striatal synaptosomes significantly decreased in 24-month-old rats comparing to 4-month-old. ASN and NAC peptide at 10 microM concentration inhibited DAT activity by 30%. Both molecules evoked intrasynaptosomal generation of reactive oxygen species measured by fluorogenic probe, 2'7'-dichlorofluorescin diacetate. In addition, ASN activated striatal cytosolic nitric oxide synthase (NOS) by 20%. Nitric oxide (NO) donor, sodium nitroprusside (SNP) (10 microM) and oxidative stress evoked by FeCl2 (25 microM) reduced [3H]DA uptake by 28 and 41%, respectively. Potent antioxidants: Trolox and 4-hydroxy-Tempo had no effect on DAT function but NOS inhibitor Nomega-nitro-L-arginine (100 microM), prevented ASN-evoked DAT down-regulation. These data indicated an important role of ASN in alteration of DA synaptic homeostasis, probably by NO mediated DAT alteration.
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PMID:Alpha-synuclein and its neurotoxic fragment inhibit dopamine uptake into rat striatal synaptosomes. Relationship to nitric oxide. 1654

Alzheimer's disease (AD) and Parkinson's disease (PD) share several pathological mechanisms. The parallels between amyloid beta (Abeta) in AD and alpha-synuclein in PD have been discussed in several reports. However, studies of the last few years show that Abeta also shares several important characteristics with neuromelanin (NM), whose role in PD is emerging. First, both molecules accumulate with aging, the greatest risk factor for AD and PD. Second, in spite of their different structures, Abeta and NM have similar characteristics that could also lead to neuroprotection. Metals are required to catalyze their formation and they can bind large amounts of these metals, generating stable complexes and thus playing a protective role against metal toxicity. Moreover, they may be able to remove toxic species such as oligopeptides and excess cytosolic dopamine. Third, both Abeta and NM have been implicated in parallel aspects of the neuronal death that underlies AD and PD, respectively. For example, both molecules can activate microglia, inducing release of toxic factors such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO). A careful analysis of these parallel effects of Abeta and NM, including their seemingly paradoxical ability to participate in both cell death and protection, may lead to an improved understanding of the roles of these molecules in neurodegeneration and also provide insights into possible parallels in the pathological mechanisms underlying AD and PD.
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PMID:Amyloid beta and neuromelanin--toxic or protective molecules? The cellular context makes the difference. 1668 9

Brain mononuclear phagocyte (perivascular macrophage and microglia, MG) inflammatory neurotoxins play a principal role in the pathogenesis of Parkinson's disease; chief among these are reactive oxygen species (ROS). We posit that aggregated, misfolded and oxidized alpha-synuclein (a major constituent of Lewy bodies), released or secreted from dying dopaminergic neurons, induces microglial ROS production that is regulated by ion channels and as such affects disease progression. To address this hypothesis, we performed patch clamp recordings of outward ionic currents in murine microglia and characterized their links to ROS production during alpha-synuclein stimulation. Aggregated nitrated alpha-synuclein induced ROS production in a dose-dependent manner that was inhibited by voltage-gated potassium current blockade, and to a more limited degree, by chloride current blockade. Interestingly, ROS produced in MG primed with tumor necrosis factor alpha and activated with phorbol myristate acetate was attenuated by voltage-gated potassium current blockade and more completely by chloride current blockade. In contrast, amyloid beta or cell membrane extract failed to induce microglial ROS production. Similar results were obtained using bone marrow-derived macrophages. The association of ROS production with specific plasma membrane ion currents provides a link between regulation of microglial ion transport and oxygen free radical production. Understanding these linkages may lead to novel therapeutics for Parkinson's disease where modulation of redox-related stress may slow disease progression.
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PMID:Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson's disease. 1724 Nov 61

To evaluate variations in amyloid beta (Abeta) peptide pattern in cerebrospinal fluid (CSF) in neurodegenerative disorders. A recently established quantitative urea-based Abeta-sodium-dodecylsulfate-polyacrylamide-gel-electrophoresis with western immunoblot (Abeta-SDS-PAGE/immunoblot) revealed a highly conserved Abeta peptide (Abeta1-37, 1-38, 1-39, 1-40, 1-42) pattern in CSF. We asked whether the variation might be useful to further elucidate the overlap between or distinctions among neurodegenerative diseases in Abeta-processing. We used the Abeta-SDS-PAGE/immunoblot to investigate CSF for disease-specific Abeta peptide patterns. CSF samples from 96 patients with mainly clinically diagnosed Alzheimer's disease (n = 15), progressive supranuclear palsy (n = 20), corticobasal degeneration (n = 12), Parkinson's disease (n = 11), multiple systems atrophy (n = 18), and dementia with Lewy-bodies (n = 20) were analysed as well a comparison group (n = 19). The Abeta peptide patterns varied between tauopathies and synucleinopathies and between all diseases and the comparison group, possibly due to the influence of tau and alpha-synuclein on Abeta-processing.
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PMID:Tauopathies and synucleinopathies: do cerebrospinal fluid beta-amyloid peptides reflect disease-specific pathogenesis? 1731 5


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