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 filaments are the central component of intracytoplasmic inclusion bodies characteristic of Parkinson's disease (PD) and related disorders. Metals are the significant etiological factors in PD, and their interaction with alpha-synuclein affect dramatically the kinetics of fibrillation. Currently, we have investigated the influence of Cu(II) and Fe(III) on alpha-synuclein fibril formation. Cu(II) and Fe(III) selectively and differentially induced the formation of discrete alpha-synuclein fibrillar species. Transmission electron microscopy was used to monitor the aggregation state of alpha-synuclein (wild-type, A30P, A53T, and E46K) after 60h with stirring at 37 degrees C in the presence and absence of metal ions. Cu(II) has induced thin long network-like fibrils with the wild-type of alpha-synuclein, while the mutant, showed amorphous aggregates with no fibrillar forms. Fe(III) induced short and thick fibrils with both wild and mutant forms and were similar to alpha-synuclein fibrils incubated without metal ion. The present study illustrates the metal-specific fibril morphology, and has relevance in understanding the role of metals in neurodegeneration.
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PMID:Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study. 1771 65

A fixed ligand (FL) version of the kinetic method was applied to rapid, simple, and accurate chiral analysis of DOPA, which is an important drug used for treatment of Parkinson's disease. Singly charged clusters containing the transition metal ion Cu(II), pyridyl ligands which serve as a fixed ligand, some amino acid as a reference, and the analyte DOPA were generated by electrospray ionization. The cluster ion of interest was mass-selected, and the kinetics of its competitive unimolecular dissociations was investigated in an ion trap mass spectrometer. The chiral selectivity (R(chiral)), the ratio of the two fragment ion abundances when the cluster contains one pure enantiomer of the analyte expressed relative to that for the other enantiomer, varies with fixed ligands, references, and transition metals. Chiral discrimination was optimized in 1,10-phenanthroline as a FL, L-Phe and L-Pro as a reference, and Cu(II) as a central metal ion. Quantitative determinations of the enantiomeric composition of DOPA were achieved using two-point calibration curves. The linear relationship between the logarithm of the fragment ion abundance ratio (ln R) and enantiomeric compositions (ee%) of the DOPA allows the determination of the chiral purity of enantiomeric mixtures.
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PMID:Determination of enantiomeric compositions of DOPA by tandem mass spectrometry using the kinetic method with fixed ligands. 1830 68

Variations in tryptophan fluorescence intensities confirm that copper(II) interacts with alpha-synuclein, a protein implicated in Parkinson's disease. Trp4 fluorescence decay kinetics measured for the F4W protein show that Cu(II) binds tightly (Kd 100 nM) near the N-terminus at pH 7. Work on a F4W/H50S mutant indicates that a histidine imidazole is not a ligand in this high-affinity site.
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PMID:Copper(II) binding to alpha-synuclein, the Parkinson's protein. 1846 59

6-Hydroxydopamine (6-OHDA) is a neurotoxin to produce an animal model of Parkinson's disease. 6-OHDA increased the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG), a biomarker of oxidatively damaged DNA, and induced apoptosis in human neuroblastoma SH-SY5Y cells. Iron or copper chelators inhibited 6-OHDA-induced 8-oxodG formation and apoptosis. Thus, iron and copper are involved in the intracellular oxidatively generated damage to DNA, a stimulus for initiating apoptosis. This study examined DNA damage caused by 6-OHDA plus metal ions using (32)P-5'-end-labelled DNA fragments. 6-OHDA increased levels of oxidatively damaged DNA in the presence of Fe(III)EDTA or Cu(II). Cu(II)-mediated DNA damage was stronger than Fe(III)-mediated DNA damage. The spectrophotometric detection of p-quinone and the scopoletin method showed that Cu(II) more effectively accelerated the 6-OHDA auto-oxidation and H(2)O(2) generation than Fe(III)EDTA. This study suggests that copper, as well as iron, may play an important role in 6-OHDA-induced neuronal cell death.
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PMID:Mechanism of metal-mediated DNA damage and apoptosis induced by 6-hydroxydopamine in neuroblastoma SH-SY5Y cells. 1865 80

The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. Protein-metal interactions play a critical role in AS aggregation and might represent the link between the pathological processes of protein aggregation and oxidative damage. Our previous studies established a hierarchy in AS-metal ion interactions, where Cu(II) binds specifically to the protein and triggers its aggregation under conditions that might be relevant for the development of PD. In this work, we have addressed unresolved structural details related to the binding specificity of Cu(II) through the design of site-directed and domain-truncated mutants of AS and by the characterization of the metal-binding features of its natural homologue beta-synuclein (BS). The structural properties of the Cu(II) complexes were determined by the combined application of nuclear magnetic resonance, electron paramagnetic resonance, UV-vis, circular dichroism spectroscopy, and matrix-assisted laser desorption ionization mass spectrometry (MALDI MS). Two independent, noninteracting copper-binding sites with significantly different affinities for the metal ion were detected in the N-terminal regions of AS and BS. MALDI MS provided unique evidence for the direct involvement of Met1 as the primary anchoring residue for Cu(II) in both proteins. Comparative spectroscopic analysis of the two proteins allowed us to deconvolute the Cu(II) binding modes and unequivocally assign the higher-affinity site to the N-terminal amino group of Met1 and the lower-affinity site to the imidazol ring of the sole His residue. Through the use of competitive chelators, the affinity of the first equivalent of bound Cu(II) was accurately determined to be in the submicromolar range for both AS and BS. Our results prove that Cu(II) binding in the C-terminal region of synucleins represents a nonspecific, very low affinity process. These new insights into the bioinorganic chemistry of PD are central to an understanding of the role of Cu(II) in the fibrillization process of AS and have implications for the molecular mechanism by which BS might inhibit AS amyloid assembly.
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PMID:Site-specific interactions of Cu(II) with alpha and beta-synuclein: bridging the molecular gap between metal binding and aggregation. 1869 89

Parkinson's disease (PD) is referred to as idiopathic disorder, which means that its causes have not been found yet. However, a few processes such as oxidative stress, protein aggregation and mitochondrial dysfunction are suspected to lead to the atrophy and death of substantia nigra (SN) neurons in case of this neurodegenerative disorder. Cu is a trace element whose role in the pathogenesis of PD is widely discussed. The investigation of Cu oxidation state inside single nerve cells from SN of PD and control cases may shed some new light on the role of this element in PD. The differences in Cu chemical state were investigated with the use of X-ray absorption near edge structure (XANES) spectroscopy. The least-square fitting method was applied for the analysis of XANES spectra. The comparison of the positions of white line, multiple scattering and pre-edge peak maximum at the energy scale did not reveal the existence of differences in Cu chemical state between PD and control samples. However, it was found that most of the Cu inside SN neurons occurs in tetrahedral environment and probably as Cu(II).
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PMID:Study of Cu chemical state inside single neurons from Parkinson's disease and control substantia nigra using the micro-XANES technique. 1875 93

Tetrahydroisoquinoline (TIQ) derivatives are putative neurotoxins that may contribute to the degeneration of dopaminergic neurons in Parkinson's disease. One TIQ, norsalsolinol (NorSAL), is present in dopamine-rich areas of human brain, including the substantia nigra. Here, we demonstrate that NorSAL reduces cell viability and induces apoptosis via cytochrome c release and caspase 3 activation in SH-SY5Y human neuroblastoma cells. Cytochrome c release, caspase 3 activation, and apoptosis induction were all inhibited by the antioxidant N-acetylcysteine. Thus, reactive oxygen species (ROS) contribute to apoptosis induced by NorSAL. Treatment with NorSAL also increased levels of oxidative damage to DNA, a stimulus for apoptosis, in SH-SY5Y. To clarify the mechanism of intracellular DNA damage, we examined the DNA damage caused by NorSAL using (32)P-5'-end-labeled isolated DNA fragments. NorSAL induced DNA damage in the presence of Cu(II). Catalase and bathocuproine, a Cu(I) chelator, inhibited this DNA damage, suggesting that ROS such as the Cu(I)-hydroperoxo complex derived from the reaction of H(2)O(2) with Cu(I), promote DNA damage by NorSAL. In summary, NorSAL-generated ROS induced oxidative DNA damage, which led to caspase-dependent apoptosis in neuronal cells.
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PMID:The mechanisms of oxidative DNA damage and apoptosis induced by norsalsolinol, an endogenous tetrahydroisoquinoline derivative associated with Parkinson's disease. 1901 44

The Cu(II)-alpha-synuclein interaction has been invoked as an important process in the pathogenesis of Parkinson's disease. Herein, we report binding constants and stoichiometry under near-physiological conditions for the binding of Cu(II) to human alpha-synuclein. Specifically, we compare the binding of Cu(II) to wild-type (WT) protein and two separate single mutation proteins that are associated with familial Parkinson's diseases: A30P and A53T. Cu(II) binds to all three alpha-synuclein proteins with a 1:1 stoichiometry. The Cu(II) binding constants, however, vary among the proteins studied. Cu(II) binding to WT and A53T at 37 degrees C is similar with a pH-dependent binding constant (K) of approximately 2.4 x 10(9) and approximately 4.8 x 10(9) M(-1) at pH 7.2 and 7.4, respectively. Cu(II) binding to A30P, however, exhibits two binding constants. The major binding site of A30P, characteristic of >90% of the bound Cu(II), has binding constants of 1.6 x 10(9) and 3.6 x 10(9) M(-1) at pH 7.2 and 7.4, respectively, slightly lower ( approximately 70%) than that characteristic of WT or A53T at the corresponding pH. The second less populated binding exhibited by A30P has a large binding constant, approximately 10(10) M(-1). Our size exclusion analysis ruled out the contribution of protofibrils to the strong Cu(II) binding. Previous studies indicated that A30P had a larger proportion of intermediate species (e.g., small oligomeric species, such as dimers and trimers) relative to WT and A53T. Thus, we propose that the high affinity site is attributed to the binding of Cu(II) to those small oligomeric species.
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PMID:Binding of Cu(II) to human alpha-synucleins: comparison of wild type and the point mutations associated with the familial Parkinson's disease. 1954 59

Parkinson's disease has been long linked to environmental factors, such as transition metals and recently to alpha-synuclein, a presynaptic protein. Using tryptophan-containing peptides, we identified the minimal Cu(II)-binding sequence to be within the first four residues, MDV(F/W), anchored by the alpha-amino terminus. In addition, mutant peptide 1-10 (Lys --> Arg) verified that neither Lys6 nor Lys10 are necessary for Cu(II) binding. Interestingly, Trp4 excited-state decay kinetics measured for peptides and proteins reveal two quenching modes, possibly arising from two distinct Cu(II)-polypeptide structures.
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PMID:Identification of the minimal copper(II)-binding alpha-synuclein sequence. 1978 Jun 17

Alpha-synuclein (alpha-syn), a presynaptic protein implicated in Parkinson's disease, binds copper(II) ion (1:1) with submicromolar affinity in vitro. Insights on the molecular details of soluble- and fibrillar-Cu-alpha-syn are gained through X-ray absorption spectroscopy. Our results indicate that the copper coordination environment (3-to-4 N/O ligands, average Cu-ligand distance approximately 1.96 A) exhibits little structural rearrangement upon amyloid formation in spite of the overall polypeptide conformational change from disordered-to-beta-sheet. Interestingly, we find that some population of Cu(II)-alpha-syn reduces to Cu(I)-alpha-syn in the absence of O(2). This autoreduction event appears diminished in the presence of O(2) suggestive of preceding Cu(I)/O(2) chemistry. Evidence for generation of reactive oxygen species is obtained by the observation of new emission features attributed to dityrosine cross-links in fibrillar samples.
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PMID:Evidence for copper-dioxygen reactivity during alpha-synuclein fibril formation. 2042 81


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