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)

Choline acetyltransferase (ChAT) activity, the sedimentation and solubility forms of acetylcholinesterase (AChE) as well as total (3H-quinuclidinyl benzilate, QNB) and M1 (3H-pirenzepine, PZ) muscarinic binding were investigated in the temporal cortex (TC) and nucleus caudatus (NC) of both non-demented and demented parkinsonian patients and controls. ChAT activity and low-salt-soluble and detergent-soluble AChE were lower in the TC of demented patients with Parkinson's disease than in controls. ChAT activity and the solubility forms of AChE in the NC did not differ between controls and parkinsonian patients. In the TC, the activity of the intermediate form of AChE was lower in parkinsonian patients, but the activity of the light form of AChE did not differ between controls and parkinsonian patients. In the TC of patients with Parkinson's disease the Bmax of 3H-QNB binding was slightly higher than in controls, but the Bmax of 3H-PZ binding did not differ between controls and parkinsonian patients. In the NC the Bmax of 3H-QNB binding was unchanged compared to that of the controls. The concomitant decrease of ChAT with soluble as well as membrane-bound tetrameric AChE suggests a close relationship between ChAT and tetrameric form of AChE. M1 receptors (3H-PZ binding sites) are not affected in the TC, but are decreased in the NC of demented parkinsonian patients. This decrease may be secondary to the loss of dopaminergic neurons projecting from the substantia nigra to the striatum.
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PMID:Different forms of brain acetylcholinesterase and muscarinic binding in Parkinson's disease. 272 71

Cells from a human neuroblastoma cell line (SH-SY5Y) have been used to examine their potential suitability as donor cells for neural transplantation. Grafts of SH-SY5Y cells were placed in the basal ganglia of the rat brain 7 days after kainic acid lesions of the striatum. The animals were killed 4 or 8 weeks following grafting, and light and electron microscopic studies showed that the graft formed a well-vascularized compact mass of cells in the host brain. At both time points grafted cells showed evidence of cellular differentiation with process formation, especially at the graft-host interface where there was intermingling of graft and host neuronal process. Electron microscopic studies showed that graft cell processes containing irregularly-shaped, clear vesicles or membrane-bound dense core vesicles, established regions of specialized contact with other graft cells and formed close associations with host neuronal processes. There was little difference between the grafts of different ages, except that in the older grafts there were early signs of neurodegeneration. Since the SH-SY5Y cells used in these grafts express the enzyme tyrosine hydroxylase and synthesize dopamine in vitro, these cells were used in the hope that they may potentially be useful for repairing lesions in the dopamine pathway, such as that seen in Parkinson's disease. Our behavioural studies show that grafting SH-SY5Y cells into the striatum of rats with 6-hydroxydopamine lesions of the median forebrain bundle result in a reduction of amphetamine-induced rotation. However, this was unlikely to be due to dopamine release since there was no tyrosine hydroxylase immunoreactivity seen in the region of the grafts. Thus grafted human neuroblastoma cells survive, establish specialized morphological associations with graft and host processes and improve behavioural deficits resulting from 6-hydroxydopamine lesions. We suggest that grafted differentiated human neuroblastoma cells can interact with cells in the host brain with beneficial effects, and that in the medium-term, neuroblastoma grafts will make useful models for examining graft-host interactions. However, the presence of early degenerative changes in the older grafts suggests that neuroblastoma cells may not be suitable for long-term neural transplantation therapy for neurodegenerative diseases.
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PMID:The morphology of human neuroblastoma cell grafts in the kainic acid-lesioned basal ganglia of the rat. 759 66

High nonphysiological doses of l-dopa are administered to Parkinson's disease (PD) patients, to replenish the depleted dopamine (DA). A large portion of the administered L-dopa and the newly formed DA undergoes methylation by reacting with S-adenosyl-L-methionine (SAM). In the process SAM, as well as L-dopa and DA, is utilized and great demands are placed on the transmethylation system. In this study we investigated whether L-dopa increases the transmethylation process by inducing methionine adenosyl transferase (MAT), the enzyme that produces SAM, and catechol-O-methyl transferase (COMT), the enzyme that transfers the methyl group from SAM to L-dopa and DA. Swiss Webster mice were injected with L-dopa, four times/day, for 1 to 16 days. Brain DA, 3-O-methyldopa (3-OMD), SAM, S-adenosylhomocysteine (SAH), MAT, and COMT were measured following a 24-h withdrawal period. An increase of 264% of brain DA occurred at days 2 and 3 after which it tapered to about 164% of control. The brain level of 3-OMD increased to 870% of the control. SAM was increased by 44% after the sixth day and SAH level was about double after the second day. After day 3, MAT activity was increased by about 35%. Western blot analysis showed that MAT is more clearly characterized in 10% mercaptoethanol reducing buffer in which 31.5-, 38- (beta), and 48-kDa (alpha1/alpha2) subunits were distinctly revealed. The induction of the 38-kDa and, more prominently, the 48-kDa subunits of MAT and the potential transactivator proteins of MAT, c-Jun/AP-1, was evident by day 6. The 31.5-kDa subunit was downregulated. COMT was detected as 24.7-, 30-, and 47.5-kDa bands in the brain, consistent with the membrane-bound COMT I (MB-COMT) and the dimeric COMT II. The 24.7- and the 30-kDa MB-COMT bands were induced in the brain by day 6 and peaked on day 9. The highlight of the study is the fact that L-dopa induces the enzymes MAT and COMT. In addition, the downturn in brain DA after the sixth day coincides with the increase in SAM and the 48-kDa MAT protein. Thus, during PD treatment with L-dopa the induction of MAT and COMT is likely to occur and in turn increase the methylation and reduction of L-dopa and DA that may help cause the tolerance or the wearing-off effect developed to L-dopa.
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PMID:L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. 1152 Jan 27

Nicotinic acetylcholine receptors (nAChRs) are membrane-bound, pentameric ligand-gated ion channels associated with a variety of human disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, and pain. Most known nAChRs contain an unusual eight-membered disulfide-containing cysteinyl-cysteine ring, ox-[Cys-Cys], as does the soluble acetylcholine binding protein (AChBP) found in the snail Lymnaea stagnalis. The cysteinyl-cysteine ring is located in a region implicated in ligand binding, and conformational changes involving this ring may be important for modulation of nAChR function. We have studied the preferred conformations of Ac-ox-[Cys-Cys]-NH2 by NMR in water and computationally by Monte Carlo simulations using the OPLS-AA force field and GB/SA water model. ox-[Cys-Cys] adopts four distinct low-energy conformers at slightly above 0 degrees C in water. Two populations are dependent on the peptide omega2 dihedral angle, with the trans amide favored over the cis amide by a ratio of ca. 60:40. Two ox-[Cys-Cys] conformers with a cis amide bond (C+ and C-) differ from each other primarily by variation of the chi3 dihedral angle, which defines the orientation of the helicity about the S-S bond (+/- 90 degrees ). Two trans amide conformers have the same S-S helicity (chi3 approximately -90 degrees ), but are distinguished by a backbone rotation about phi2 and psi1 (T- and T'-). The ratio of T-/T'-/C+/C- is 47:15:29:9. The orientation of the pendant moieties from the eight-membered ring is more compact for the major trans conformer (T-) than for the extended conformations adopted by T'-, C+, and C-. These conformational preferences are also observed in tetrapeptide and undecapeptide fragments of the human alpha7 subtype of the nAChR that contains the ox-[Cys-Cys] unit. Conformer T- is nearly identical to the conformation seen in the X-ray structure of ox-[Cys(187)-Cys(188)] found in the unliganded AChBP, and is a Type VIII beta-turn.
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PMID:Conformational analysis of the eight-membered ring of the oxidized cysteinyl-cysteine unit implicated in nicotinic acetylcholine receptor ligand recognition. 1174 32

The discovery of mutations in the gene for alpha-synuclein in familial Parkinson's disease (PD) has led to an increased interest in this pre-synaptic protein. Synphilin-1, a potential synuclein-binding protein, was cloned using yeast two-hybrid assays. The function of synphilin-1 is currently unknown, although it has been reported to be present along with alpha-synuclein in Lewy bodies in PD. In the present study, we monitored synphilin-1 aggregation directly using fusion proteins of synphilin-1 and green fluorescent protein (EGFP). Transfection of synphilin-EGFP fusion proteins formed cytoplasmic inclusions in HEK293 cells. Although these inclusions overlapped with the distribution of alpha-synuclein, they were unlike Lewy bodies in that they were not eosinophilic, and instead were membrane-bound, lipid-rich cytoplasmic inclusions.
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PMID:Transfected synphilin-1 forms cytoplasmic inclusions in HEK293 cells. 1174 67

Defects of the NADH dehydrogenase complex are predominantly manifested in mitochondrial diseases and are significantly associated with the development of many late onset neurological disorders such as Parkinson's disease. Here we describe an immunocapture procedure for isolating this multisubunit membrane-bound complex from human tissue. Using small amounts of immunoisolated protein, one-dimensional and two-dimensional gel electrophoresis, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) peptide mass finger printing (PMF), and nanoflow liquid chromatography mass spectrometry/mass spectrometry (LC-MS/MS), we can resolve and identify the human homologues of 42 polypeptides detected so far in the more extensively studied beef heart complex I. These polypeptides include the GRIM-19 protein, which is claimed to be involved in apoptosis, a polypeptide first identified by gene screening as a neuronal protein, as well as a protein thought to be in differentiation linked processes. The concordance of data from human and bovine complex I isolated by different procedures adds to the certainty that these novel proteins of seemingly diverse function are a part of complex I.
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PMID:The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification. 1261 91

Parkinson's disease is the second most common neurodegenerative disorder, and the cause is unknown; however, substantial evidence implicates the aggregation of alpha-synuclein as a critical factor in the etiology of the disease. alpha-Synuclein is a relatively abundant brain protein of unknown function, and the purified protein is intrinsically unfolded. The amino acid sequence has seven repeats with an apolipoprotein lipid-binding motif, which are predicted to form amphiphilic helices. We have investigated the interaction of alpha-synuclein with lipid vesicles of different sizes and properties by monitoring the effects on the conformation of the protein and the kinetics of fibrillation. The nature of the interaction of alpha-synuclein with vesicles was highly dependent on the phospholipid composition, the ratio of alpha-synuclein to phospholipid, and the size of the vesicles. The strongest interactions were between alpha-synuclein and vesicles composed of 1,2-dipalmitoyl-sn-glycero-3-phosphate/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phospho-RAC-(1-glycerol)/1,2-dipalmitoyl-sn-glycero-3-phosphocholine and involved formation of helical structure in alpha-synuclein. A strong correlation was observed between the induction of alpha-helix in alpha-synuclein and the inhibition of fibril formation. Thus, helical, membrane-bound alpha-synuclein is unlikely to contribute to aggregation and fibrillation. Given that a significant fraction of alpha-synuclein is membrane-bound in dopaminergic neurons, this observation has significant physiological significance.
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PMID:Lipid binding inhibits alpha-synuclein fibril formation. 1262 Oct 30

Green tea extract and its main polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) possess potent neuroprotective activity in cell culture and mice model of Parkinson's disease. The central hypothesis guiding this study is that EGCG may play an important role in amyloid precursor protein (APP) secretion and protection against toxicity induced by beta-amyloid (Abeta). The present study shows that EGCG enhances (approximately 6-fold) the release of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) into the conditioned media of human SH-SY5Y neuroblastoma and rat pheochromocytoma PC12 cells. sAPPalpha release was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790, which indicated mediation via alpha-secretase activity. Inhibition of protein kinase C (PKC) with the inhibitor GF109203X, or by down-regulation of PKC, blocked the EGCG-induced sAPPalpha secretion, suggesting the involvement of PKC. Indeed, EGCG induced the phosphorylation of PKC, thus identifying a novel PKC-dependent mechanism of EGCG action by activation of the non-amyloidogenic pathway. EGCG is not only able to protect, but it can rescue PC12 cells against the beta-amyloid (Abeta) toxicity in a dose-dependent manner. In addition, administration of EGCG (2 mg/kg) to mice for 7 or 14 days significantly decreased membrane-bound holoprotein APP levels, with a concomitant increase in sAPPalpha levels in the hippocampus. Consistently, EGCG markedly increased PKCalpha and PKC in the membrane and the cytosolic fractions of mice hippocampus. Thus, EGCG has protective effects against Abeta-induced neurotoxicity and regulates secretory processing of non-amyloidogenic APP via PKC pathway.
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PMID:Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (-)-epigallocatechin-3-gallate. 1267 Aug 74

Abnormal accumulation of alpha-synuclein in Lewy bodies is a neuropathological hallmark of both sporadic and familial Parkinson's disease (PD). Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic cell death occurs remains unknown. We investigated transcriptional changes in neuroblastoma cell lines transfected with either normal or mutant (A30P or A53T) alpha-synuclein using microarrays, with confirmation of selected genes by quantitative RT-PCR. Gene products whose expression was found to be significantly altered included members of diverse functional groups such as stress response, transcription regulators, apoptosis-inducing molecules, transcription factors and membrane-bound proteins. We also found evidence of altered expression of dihydropteridine reductase, which indirectly regulates the synthesis of dopamine. Because of the importance of dopamine in PD, we investigated the expression of all the known genes in dopamine synthesis. We found co-ordinated downregulation of mRNA for GTP cyclohydrolase, sepiapterin reductase (SR), tyrosine hydroxylase (TH) and aromatic acid decarboxylase by wild-type but not mutant alpha-synuclein. These were confirmed at the protein level for SR and TH. Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor.
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PMID:Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines. 1271 27

The aggregation of alpha-synuclein is believed to be a critical factor in the etiology of Parkinson's disease. alpha-Synuclein is an abundant neuronal protein of unknown function, which is enriched in the presynaptic terminals of neurons. Although alpha-synuclein is found predominantly in the cytosolic fractions, membrane-bound alpha-synuclein has been suggested to play an important role in fibril formation. The effects of alpha-synuclein on lipid bilayers of different compositions were determined using fluorescent environment-specific probes located at various depths. alpha-Synuclein-membrane interactions were found to affect both protein and membrane properties. Our results indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of the protein with the bilayer, and lead to disruption of the membrane. The latter was observed by atomic force microscopy and fluorescent dye leakage from vesicles. The kinetics of alpha-synuclein fibril formation were significantly affected by the protein association and subsequent membrane disruption, and reflected the conformation of alpha-synuclein. The ability of alpha-synuclein to disrupt membranes correlated with the binding affinity of alpha-synuclein for the particular membrane composition, and to the induced helical conformation of alpha-synuclein. Protofibrillar or fibrillar alpha-synuclein caused a much more rapid destruction of the membrane than soluble monomeric alpha-synuclein, indicating that protofibrils (oligomers) or fibrils are likely to be significantly neurotoxic.
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PMID:The association of alpha-synuclein with membranes affects bilayer structure, stability, and fibril formation. 1288 75


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