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)

The cerebrospinal fluid of eight patients with Parkinson's disease who underwent adrenal medullary autotransplantation was analyzed using SDS-polyacrylamide gel electrophoresis. A protein, subsequently identified as prealbumin, was noted to change in concentration over the intraoperative to 18-month postoperative time course. The qualitative changes observed on visual inspection were confirmed and quantified using laser densitometry. The concentration of prealbumin increased by an average of 90% when the intraoperative and 12-month samples were compared. This increase persisted at 18 months. The ratio of prealbumin to albumin also increased from intraoperative to 12 months by an average of 56%. This suggests that the increases in PA are the result of choroid plexus activation rather than a nonspecific breakdown of the blood-brain barrier. Given the association of prealbumin with other nervous system diseases, as well as its known ability to bind multiple substances, these findings may have important implications. Alterations in prealbumin may be responsible for the improvement seen in some patients who receive adrenal medullary autotransplants. Alternatively, prealbumin may be implicated in the pathophysiology of Parkinson's disease.
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PMID:Alterations in prealbumin concentration after adrenal autotransplantation for Parkinson's disease. 211 May 29

Neurogenic orthostatic hypotension is a severely disabling condition due to deficient peripheral vasoconstrictor tone in response to the upright position and is characterized by a decrease in blood pressure upon standing associated with symptoms of lightheadedness, dizziness, visual "white-out", weakness, lack of energy, near syncope or even syncope. Previous pharmacologic treatment of neurogenic orthostatic hypotension has been problematic. Midodrine, a new specific alpha-1-agonist has been shown to produce arteriolar constriction and decrease in venous pooling via a constriction of venous capacitance vessels. Therefore, a recent multicenter study evaluated the safety and efficacy of midodrine therapy in 97 patients with neurogenic orthostatic hypotension due to various etiologies: Shy Drager syndrome (No. 18); Bradbury Eggleston syndrome (idiopathic orthostatic hypotension) (No. 20); diabetic autonomic neuropathy (No. 27); Parkinson's disease (No. 22); and miscellaneous (No. 10). Following one week of placebo therapy, the patients were randomized into 4 groups for a 4 week period of time; placebo, 2.5 mg, 5 mg, or 10 mg three times daily. The BE/SDS subgroup demonstrated a 27 +/- 8% (22 mmHg) increase in standing systolic blood pressure for the 10 mg dose. Diabetics achieved a significant increase at 5 mg. Similar increases were observed for the entire group on the 10 mg dose (p < 0.001). Symptoms or fainting, blurred vision, improved energy level, standing time, and depressed feelings were also significantly improved even at lower doses (p < 0.05 or less). Side effects were mild. Therefore, midodrine is an effective and safe agent for the treatment of neurogenic orthostatic hypotension.
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PMID:Midodrine in neurogenic orthostatic hypotension. A new treatment. 769 Mar 83

Brainstem Lewy bodies (LB) are neuronal inclusions that are closely related to Parkinson's disease (PD). The filamentous component of LB from patients with PD contains biochemically altered neurofilaments (NF). Herein we have tested the hypothesis that the oxidized products of catechols may covalently crosslink NF. Neurofilaments were incubated in the presence of oxidized L-dopa, dopamine, or dopac and then analyzed by SDS-PAGE and protein staining or immunoblotting with monoclonal antibodies specific for neurofilament subunit proteins. Oxidized catechols yielded the same pattern of NF protein crosslinking as known covalent crosslinking agents. Coincubation of NF and catechols with N alpha-acetyl-L-lysine (NAL) produced strong reactivity on immunoblots probed with a polyclonal antiserum specific for NAL crosslinked to protein (antiserum 1400/3). Crosslinking of NAL to model proteins by oxidized dopac was followed by antibody capture assays using antiserum 1400/3. Increasing immunoreactivity was observed for 0.01 to 1.0 mM dopac and was augmented by Cu2+, Fe2+, Fe3+, Mn2+, or Mn3+ up to 0.1 mM. These results show that the products of catechol oxidation can covalently crosslink neurofilaments, that the crosslinking mechanism can involve lysine, and that copper, iron, and manganese ions can accelerate catechol-mediated protein crosslinking.
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PMID:Covalent crosslinking of neurofilament proteins by oxidized catechols as a potential mechanism of Lewy body formation. 774 30

The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.
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PMID:Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy. 802 94

Chromogranin A was purified from post-mortem human brain tissue, obtained at autopsy by a three step chromatography procedure to a single band purity on SDS gel electrophoresis at 68 kDa. Purified protein was further characterized by immunoblotting using a mouse anti-chromogranin A monoclonal antibody LK2H10, which recognizes the 68 kDa chromogranin A in human brain. The results demonstrate a simple protocol of preparing CgA from the human brain. Chromogranin plays a very important role in various neurological disorder and has been examined immunohistochemically in Alzheimer's disease, Parkinson's disease, Pick's disease. The procedure of purification may be useful in further defining its biological function, biochemistry and physiological significance in the central nervous system and may be useful in delineating the molecular pathology of certain neurological disorders.
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PMID:Purification and partial characterization of chromogranin-A from human brain. 909 Apr 64

MSA is a complex disorder, with regard to its pathology and cause as well as its clinical diagnosis and treatment. Although a number of clinical treatments may improve quality of life for these patients, given the widespread pathology present, symptomatic treatment, particularly that involving neurotransmitter replacement, is likely to remain difficult. Truly effective treatment for these patients is likely to depend on an understanding of the underlying pathogenic mechanisms and methods to halt or reverse disease progression. A firm understanding of the classification of these disorders is the first step to understanding the relevant pathogenic mechanisms. The finding of intracytoplasmic glial inclusion bodies provides a compelling piece of evidence that SND, OPCA, and SDS do, in fact, belong to one nosologic entity. These inclusions do not seem to be present in familial cases of OPCA; thus, they may provide a means to improve diagnostic specificity as well as sensitivity. With the ability to define clearly the entity of MSA, an understanding of the pathophysiology can be developed along with other degenerative neurologic diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease.
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PMID:Multiple system atrophy. 1009 84

Transplantation of porcine embryonic brain cells, including dopaminergic neurons, from ventral mesencephalon (VM) is considered a potential treatment for patients with Parkinson's disease. In the present study, we characterized the distribution among VM cells of the major porcine endothelial xenoantigen, the Galalpha1,3Gal epitope, and evaluated the cytotoxic effect of anti-Galalpha1,3Gal antibody-depleted and nondepleted human AB serum on VM cells. Overall levels of Galalpha1,3Gal-epitope expression was very low on the VM cell population using Bandeiraea simplicifolia IB(4) lectin staining of resuspended VM cells in flow cytometric analyses or staining of SDS-PAGE-separated, solubilized VM cell membrane proteins in Western blot analyses. Lectin-histochemical staining of sections of pig embryonal VM regions with BSA IB(4) lectin showed staining restricted to endothelial cells and microglia. In the presence of complement, both nondepleted and anti-Galalpha1,3Gal antibody-depleted AB sera were shown to be cytotoxic to VM cells as assessed in microcytotoxicity- and flow cytometry-based cytotoxicity assays. Purified IgM and IgG were both cytotoxic in the presence of complement. Three major VM cell membrane antigens of approximately 210, 105, and 50 kDa were reactive with natural IgM antibodies present in pooled human AB sera. Thus, antibody-dependent cytotoxicity may contribute to pig to human brain cell xenorejection, necessitating donor tissue modifications prior to a more widespread utilization of neural tissue xenografting.
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PMID:Human natural antibodies cytotoxic to pig embryonic brain cells recognize novel non-Galalpha1,3Gal-based xenoantigens. 1050 7

alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.
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PMID:Non-Abeta component of Alzheimer's disease amyloid (NAC) revisited. NAC and alpha-synuclein are not associated with Abeta amyloid. 1066 11

Intracellular proteinaceous aggregates are hallmarks of many common neurodegenerative disorders, and recent studies have shown that alpha-synuclein is a major component of several pathological intracellular inclusions, including Lewy bodies in Parkinson's disease (PD) and glial cell inclusions in multiple system atrophy. However, the molecular mechanisms underlying alpha-synuclein aggregation into filamentous inclusions remain unknown. Since oxidative and nitrative stresses are potential pathogenic mediators of PD and other neurodegenerative diseases, we asked if oxidative and/or nitrative events alter alpha-synuclein and induce it to aggregate. Here we show that exposure of human recombinant alpha-synuclein to nitrating agents (peroxynitrite/CO(2) or myeloperoxidase/H(2)O(2)/nitrite) induces formation of nitrated alpha-synuclein oligomers that are highly stabilized due to covalent cross-linking via the oxidation of tyrosine to form o,o'-dityrosine. We also demonstrate that oxidation and nitration of pre-assembled alpha-synuclein filaments stabilize these filaments to withstand denaturing conditions and enhance formation of SDS-insoluble, heat-stable high molecular mass aggregates. Thus, these data suggest that oxidative and nitrative stresses are involved in mechanisms underlying the pathogenesis of Lewy bodies and glial cell inclusions in PD and multiple system atrophy, respectively, as well as alpha-synuclein pathologies in other synucleinopathies.
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PMID:Dityrosine cross-linking promotes formation of stable alpha -synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. 1074 81

alpha-Synuclein is a major component of Lewy bodies in Parkinson's disease, dementia with Lewy bodies, and glial cytoplasmic inclusions in multiple system atrophy. Increasing evidence suggests that the nitration of tyrosine residues in alpha-synuclein induced by oxidative injury is involved in the formation of inclusions characteristic to these synucleinopathies. Exposure of alpha-synuclein to peroxynitrite induces nitration of tyrosine residues, thereby forming alpha-synuclein oligomers. However, the contribution of tyrosine residues to either the nitration or the oligomerization is currently unknown. The present study used recombinant wild-type and mutant alpha-synuclein proteins to investigate the role of each alpha-synuclein tyrosine residue in the in vitro formation of alpha-synuclein oligomers under nitrative stress. Confocal microscopic analysis revealed that wild-type alpha-synuclein protein was able to accumulate and form an inclusion-like structure in the cytoplasm of living cells upon introduction by streptolysin O. Authentic peroxynitrite induced nitration of tyrosine residues in alpha-synuclein protein, as well as dimerization of alpha-synuclein. The formation of both SDS- and heat-stable dimers suggests cross-linking between nitrated tyrosine residues. Nonetheless, dimerization of alpha-synuclein proteins lacking tyrosine 125 was significantly decreased compared with alpha-synuclein proteins lacking tyrosine residues at positions 39, 133, or 136. Presumably, tyrosine 125 plays a critical role for alpha-synuclein dimerization under nitrative stress.
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PMID:Tyrosine 125 of alpha-synuclein plays a critical role for dimerization following nitrative stress. 1203 37


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