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)

We have utilized integrated technologies including separation of proteins by 2-dimensional (2-D) gel electrophoresis and identification of proteins by matrix assisted laser desorption/ionizing time of flight (MALDI-TOF) mass spectrometry to examine an array of proteins that are regulated following treatment with neurotoxin. In essence, total cellular lysates harvested from MN9D dopaminergic neuronal cells treated with 6-hydroxydopamine (6-OHDA) for various time periods were subjected to 2-D gel separation followed by an analysis of the protein spots separated. Among the several protein spots that appeared to be either up- or down-regulated following 6-OHDA treatment, MALDI-TOF mass spectrometry revealed that an ER chaperone protein, calreticulin, was upregulated in a time-dependent manner. 6-OHDA-mediated up-regulation of this protein spot was reversed to the untreated control level when MN9D cells were co-treated with a pan-caspase inhibitor or an anti-oxidant. Immunoblot analysis using anti-calreticulin antibody confirmed this phenomenon. Since accumulation of altered proteins may be relevant in Parkinson's disease, our data suggest that regulation of chaperone activity in dopaminergic neurons comprises an additional cellular response to death-inducing stimuli.
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PMID:Proteomic analysis reveals upregulation of calreticulin in murine dopaminergic neuronal cells after treatment with 6-hydroxydopamine. 1461 39

Although alpha-synuclein is the main structural component of the insoluble filaments that form Lewy bodies in Parkinson disease (PD), its physiological function and exact role in neuronal death remain poorly understood. In the present study, we examined the possible functional relationship between alpha-synuclein and several forms of matrix metalloproteinases (MMPs) in the human dopaminergic neuroblastoma (SK-N-BE) cell line. When SK-N-BE cells were transiently transfected with alpha-synuclein, it was secreted into the extracellular culture media, concomitantly with a significant decrease in cell viability. Also the addition of nitric oxide-generating compounds to the cells caused the secreted alpha-synuclein to be digested, producing a small fragment whose size was similar to that of the fragment generated during the incubation of alpha-synuclein with various MMPs in vitro. Among several forms of MMPs, alpha-synuclein was cleaved most efficiently by MMP-3, and MALDI-TOF mass spectra analysis showed that alpha-synuclein is cleaved from its C-terminal end with at least four cleavage sites within the non-Abeta component of AD amyloid sequence. Compared with the intact form, the protein aggregation of alpha-synuclein was remarkably facilitated in the presence of the proteolytic fragments, and the fragment-induced aggregates showed more toxic effect on cell viability. Moreover, the levels of MMP-3 were also found to be increased significantly in the rat PD brain model produced by the cerebral injection of 6-hydroxydopamine into the substantia nigra. The present study suggests that the extracellularly secreted alpha-synuclein could be processed via the activation of MMP-3 in a selective manner.
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PMID:Proteolytic cleavage of extracellular secreted {alpha}-synuclein via matrix metalloproteinases. 1586 97

Proteomics technologies have been widely used in the investigation of neurodegenerative and psychiatric disorders, and in particular in the detection of differences between healthy individuals and patients suffering from such diseases. Thus, brain and cerebrospinal fluid (CSF) samples from patients with Alzheimer's disease, Down syndrome, Pick's disease, Parkinson's disease, schizophrenia, and other disorders as well as brain and CSF from animals serving as models of neurological disorders have been analyzed by proteomics. 2-DE followed by MALDI-TOF-MS has been mainly applied as this proteomics approach provides the possibility of convenient quantification of protein levels and detection of post-translational modifications. About 330 unique proteins with deranged levels and modifications have been detected by proteomics approaches to be related to neurodegeneration and psychiatric disorders. They are mainly involved in metabolism pathways, cytoskeleton formation, signal transduction, guidance, detoxification, transport, and conformational changes. In this article, we provide a summary of the major contributions of proteomics technologies in the study of neurodegenerative and psychiatric diseases, in particular, in the detection of changes in protein levels and modifications related to these disorders.
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PMID:Proteomics-driven progress in neurodegeneration research. 1655 40

Recently, the introduction of 3 tesla (3T) magnetic resonance (MR) system for more sophisticated clinical applications has yielded in important benefits, especially in neuroradiology. The aim of this article is to illustrate the practical scientific applications of the 3T system in the neuroradiological filed. From the clinical point of view, we focused on the usefulness of 3T system for the diagnosis of several neurological disorders, such as brain tumors, vascular lesions, hemorrhagic lesions, acute cerebral infarcts and degenerative diseases. The greatest advantage of high-field MR system is a higher signal to noise ratio. This higher spatial resolution can provide precise anatomical information for brain tumor itself and its surrounding structures. Diffusion weighted imaging (DWI) also benefits from the higher signal to noise ratio and offers useful information for tumor characteristics. Navigation system with diffusion tensor tractgraphy is also available for surgical operation of brain tumors. Parallel imaging enables to improve the quality of tractgraphy by reducing susceptibility artifacts. 3T TOF (time-of-flight) MR angiography (MRA) demonstrates superior depiction of intracranial aneurysms compared with that of 1.5T TOF MRA. 3T TOF MRA is also useful for the evaluation and follow-up of stenoocclusive diseases including moyamoya disease. Susceptibility weighted imaging (SWI) is a BOLD (blood oxygenation level dependent)-sensitive method for visualizing anatomical features such as small cerebral veins in high detail. Therefore, 3T system has advantages for obtaining detailed, high spatial resolution images of the venous network. SWI is useful for detection of hemorrhagic lesions and early diagnosis of acute hemorrhagic infarcts. SWI also can detect embolus and evaluate functional changes showing dilatation of medullary veins in the area of acute cerebral infarcts. Neuromelanin imaging using 3T system can directly demonstrate the locus ceruleus and substantia nigra by the neuromelanin content and have the potential to become a powerful tool in Parkinson's disease and other neurodegenerative disorders with Parkinsonism. Hyperintense putaminal rim can be often observed in clinically normal subjects on fast spin echo T2-weighted images at 3T system. This finding should not be mistaken for multiple system atrophy. 3T MR system indeed offers new potential because of a substantial increase in signal intensity provided by the higher magnetic field. Routine neuroradiologic imaging would benefit from higher magnetic field. However, It is required that extended knowledge of clinical data in comparison with 1.5T system to elucidate the efficacy of 3T system in the neuroradiology.
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PMID:[Clinical applications of 3.0 T magnetic resonance system in the neuroradiological field]. 1753 73

Neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) have been associated with increased production of reactive oxygen species. In AD and PD patients, superoxide dismutase (SOD1) was also indicated as a major target of oxidative damage. In particular, in brain tissue of these patients, different SOD1 isoforms have been identified, although their functional role still remains to be elucidated. In the light of the possibility that different SOD1 entities could be expressed also in other neurodegenerative disorders, as a sort of unifying event with AD and PD, we have investigated amyotrophic lateral sclerosis (ALS) using human neuroblastoma SH-SY5Y cells with mutated SOD1 gene H46R as cellular model. 2-DE using a narrow-range IPG 4-7 strips in the first dimension and linear 15% SDS-PAGE in the second allowed to separate different SOD1 spots. MALDI-TOF MS and CapLC-MS/MS have been used for their complete identification. This is the first report in which the presence of SOD1 (iso) forms in a cellular model of ALS has been evidenced.
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PMID:Optimizing separation efficiency of 2-DE procedures for visualization of different superoxide dismutase forms in a cellular model of amyotrophic lateral sclerosis. 1798 32

Targeted quantitative proteomics by mass spectrometry aims to selectively detect one or a panel of peptides/proteins in a complex sample and is particularly appealing for novel biomarker verification/validation because it does not require specific antibodies. Here, we demonstrated the application of targeted quantitative proteomics in searching, identifying, and quantifying selected peptides in human cerebrospinal spinal fluid (CSF) using a matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (MALDI TOF/TOF)-based platform. The approach involved two major components: the use of isotopic-labeled synthetic peptides as references for targeted identification and quantification and a highly selective mass spectrometric analysis based on the unique characteristics of the MALDI instrument. The platform provides high confidence for targeted peptide detection in a complex system and can potentially be developed into a high-throughput system. Using the liquid chromatography (LC) MALDI TOF/TOF platform and the complementary identification strategy, we were able to selectively identify and quantify a panel of targeted peptides in the whole proteome of CSF without prior depletion of abundant proteins. The effectiveness and robustness of the approach associated with different sample complexity, sample preparation strategies, as well as mass spectrometric quantification were evaluated. Other issues related to chromatography separation and the feasibility for high-throughput analysis were also discussed. Finally, we applied targeted quantitative proteomics to analyze a subset of previously identified candidate markers in CSF samples of patients with Parkinson's disease (PD) at different stages and Alzheimer's disease (AD) along with normal controls.
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PMID:Application of targeted quantitative proteomics analysis in human cerebrospinal fluid using a liquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (LC MALDI TOF/TOF) platform. 1818 1

There is substantial evidence which implicates alpha-synuclein and its ability to aggregate and bind vesicle membranes as critical factors in the development of Parkinson's disease. In order to investigate the interaction between alpha-synuclein wild type (Wt) and its familial mutants, A53T and A30P with lipid membranes, we developed a novel lipid binding assay using surface enhanced laser desorption/ionisation-time of flight-mass spectrometry (SELDI-TOF MS). Wt and A53T exhibited similar lipid binding profiles; monomeric species and dimers bound with high relative affinity to the lipid surface, the latter of which exhibited preferential binding. Wt and A53T trimers and tetramers were also detected on the lipid surface. A30P exhibited a unique lipid binding profile; monomeric A30P bound with a low relative affinity, however, the dimeric species of A30P exhibited a higher binding ability. Larger order A30P oligomers were not detected on the lipid surface. Tapping mode atomic force microscopy (AFM) imaging was conducted to further examine the alpha-synuclein-lipid interaction. AFM analysis revealed Wt and its familial mutants can penetrate lipid membranes or disrupt the lipid and bind the hydrophobic alkyl self-assembled monolayer (SAM) used to form the lipid layer. The profile of these studied proteins revealed the presence of 'small features' consistent with the presence of monomeric and dimeric forms of the protein. These data collectively indicate that the dimeric species of Wt and its mutants can bind and cause membrane perturbations.
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PMID:Dimeric structures of alpha-synuclein bind preferentially to lipid membranes. 1826 56

The c.G7153A variant in the LRRK2 gene (protein effect: Gly2385Arg) is emerging as an important risk factor for Parkinson's disease (PD) in the Han Chinese and Japanese populations. The prevalence of this variant in other neurodegenerative diseases and movement disorders remains almost completely unexplored. Using MALDI-TOF, we studied the Gly2385Arg variant in a large cohort of patients with primary dystonia (n=335) and a smaller series of patients with clinically diagnosed multiple system atrophy (MSA, n=57). The Gly2385Arg variant was identified in heterozygous state in 14 patients with primary dystonia (4.18%) and in three patients with MSA (5.26%). These frequencies do not differ statistically from that reported previously by us in Taiwanese controls (5%). We conclude that the Gly2385Arg variant is not associated with primary dystonia in Taiwan, supporting the specificity of the association between this variant and PD. Whether the Gly2385Arg variant modifies the risk for MSA deserves further study in larger samples.
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PMID:Analysis of the LRRK2 Gly2385Arg variant in primary dystonia and multiple system atrophy in Taiwan. 1845 Apr 97

Despite its thorough enzymological and biochemical characterization the exact function of prolyl oligopeptidase (PO, E.C. 3.4.21.26) remains unclear. The positive effect of PO inhibitors on learning and memory in animal models for amnesia, enzyme activity measurements in patient samples and (neuro)peptide degradation studies link the enzyme with neurodegenerative disorders. The brain protein alpha-synuclein currently attracts much attention because of its proposed role in the pathology of Parkinson's disease. A fundamental question concerns how the essentially disordered protein is transformed into the highly organized fibrils that are found in Lewy bodies, the hallmarks of Parkinson's disease. Using gel electrophoresis and MALDI TOF/TOF mass spectrometry we investigated the possibility of alpha-synuclein as a PO substrate. We found that in vitro incubation of the protein with PO did not result in truncation of full-length alpha-synuclein. Surprisingly, however, we found an acceleration of the aggregation process of alpha-synuclein using turbidity measurements that was reversed by specific inhibitors of PO enzymatic activity. If PO displays this activity also in vivo, PO inhibitors might have an effect on neurodegenerative disorders through a decrease in the aggregation of alpha-synuclein.
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PMID:Prolyl oligopeptidase stimulates the aggregation of alpha-synuclein. 1857 Dec 85

Pyrroloquinoline quinone (PQQ) has been shown to play a role as an anti-oxidant in neuronal cells and prevent neuronal cell death in a rodent stroke model. DJ-1, a causative gene product for a familial form of Parkinson's disease, plays a role in anti-oxidative stress function by self-oxidation of DJ-1. In this study, the expression level and oxidation status of DJ-1 were examined in SHSY-5Y cells and primary cultured neurons treated with 6-hydroxydopamine (6-OHDA) or H(2)O(2) in the presence or absence of PQQ. The pI shift of DJ-1 to an acidic point, which was observed in SHSY-5Y cells treated with 6-OHDA, was inhibited by PQQ. TOF-MS analyses showed that while the level of a reduced form of DJ-1, one of the active forms of DJ-1, was decreased in SHSY-5Y cells treated with 6-OHDA or H(2)O(2), PQQ increased the level of the reduced form of DJ-1. These results suggest that PQQ prevents oxidative stress-induced changes in oxidative status of DJ-1. Therefore, the neuroprotective effects of PQQ on oxidative stress-induced neuronal death may be at least in part involved in increased level of an active form of DJ-1.
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PMID:Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1. 1859 68


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