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 hypothesized that levodopa with carbidopa, a common therapy for patients with Parkinson's disease, might contribute to the high prevalence of insulin resistance reported in patients with Parkinson's disease. We examined the effects of levodopa-carbidopa on glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in skeletal muscle, the predominant insulin-responsive tissue. In isolated muscle, levodopa-carbidopa completely prevented insulin-stimulated glycogen accumulation and glucose transport. The levodopa-carbidopa effects were blocked by propranolol, a beta-adrenergic antagonist. Levodopa-carbidopa also inhibited the insulin-stimulated increase in glycogen synthase activity, whereas propranolol attenuated this effect. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was reduced by levodopa-carbidopa, although Akt phosphorylation was unaffected by levodopa-carbidopa. A single in vivo dose of levodopa-carbidopa increased skeletal muscle cAMP concentrations, diminished glycogen synthase activity, and reduced tyrosine phosphorylation of IRS-1. A separate set of rats was treated intragastrically twice daily for 4 wk with levodopa-carbidopa. After 4 wk of treatment, oral glucose tolerance was reduced in rats treated with drugs compared with control animals. Muscles from drug-treated rats contained at least 15% less glycogen and approximately 50% lower glycogen synthase activity compared with muscles from control rats. The data demonstrate beta-adrenergic-dependent inhibition of insulin action by levodopa-carbidopa and suggest that unrecognized insulin resistance may exist in chronically treated patients with Parkinson's disease.
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PMID:Levodopa with carbidopa diminishes glycogen concentration, glycogen synthase activity, and insulin-stimulated glucose transport in rat skeletal muscle. 1525 32

Protein misfolding has been shown to be the direct cause of a number of highly devastating diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob syndrome, affecting the aging population globally. The deposition in tissues of amyloid fibrils is a characteristic of all these diseases, and the mechanisms by which these protein aggregates form continue to be intensively investigated. In only a fraction of cases is an underlying mutation responsible, and accordingly, what initiates amyloid formation in vivo is the major question that is addressed. In this study, we show that membranes containing phosphatidylserine (PS), a negatively charged phospholipid, induce a rapid formation of fibers by a variety of proteins, viz., lysozyme, insulin, glyceraldehyde-3-phosphate dehydrogenase, myoglobin, transthyretin, cytochrome c, histone H1, and alpha-lactalbumin. Congo red staining of these fibers yields the characteristic light green birefringence of amyloid, and fluorescent lipid tracers further reveal them to include phospholipids. Our results suggest that PS as well as other acidic phospholipids could provide the physiological low-pH environment on cellular membranes, enhancing protein fibril formation in vivo. Interestingly, all the proteins mentioned above either are cytotoxic or induce apoptosis. PS-protein interaction could be involved in the mechanism of cytotoxicity of the aggregated protein fibrils, perturbing membrane functions. Importantly, our results suggest that this process induced by acidic phospholipids may provide an unprecedented and generic connection between three current major areas of research: (i) mechanism(s) triggering amyloid formation, (ii) cytotoxicity of amyloidal protein aggregates, and (iii) mechanism(s) of action of cytotoxic proteins.
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PMID:Formation of amyloid fibers triggered by phosphatidylserine-containing membranes. 1530 28

p62 is a cellular protein that plays an adapter role in signal transduction pathways involved in such diverse biological functions as proliferation, differentiation, reaction to oxidative stress and immune response. Furthermore, p62 has recently been detected as a component of intracytoplasmic protein aggregates (inclusion bodies), which are hallmarks of a variety of chronic degenerative disorders, such as Parkinson's disease and Alzheimer's disease, but also of steatohepatitis. Here we report that p62 and insulin are co-expressed in a diffuse fashion in beta cells in normal human pancreas as well as in primary chronic pancreatitis and in normal pancreas from mouse and swine. In contrast, p62 protein is absent from, or only focally and very weakly expressed in, insulinomas, glucagonomas or non-functioning pancreatic neuroendocrine tumours or carcinomas that express insulin or other pancreatic as well as extrapancreatic hormones. Although the biological function of p62 in beta cells is unknown, the co-expression of p62 and insulin in non-neoplastic beta cells suggests that, in the beta cell, p62 may play a role in specific insulin-related signalling. Since p62 may also be involved in pro-apototic signal transduction, the loss of p62 expression in neuroendocrine neoplasms of the pancreas may render the tumour cells less sensitive to pro-apototic signals. Further research is necessary to elucidate the role of p62 in beta cell-specific signal transduction.
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PMID:p62 protein is expressed in pancreatic beta cells. 1592 99

LGR8 was recently identified as a cognate receptor for insulin-like peptide-3 (INSL3), and INSL3-LGR8 signaling is best known for its role in testis descent during development. LGR8 mRNA has been detected in various human tissues including brain, but the regional and cellular distribution of LGR8 expression in the mammalian central nervous system is unknown. Therefore, in this study we investigated the presence and localization of LGR8 mRNA in rat brain using reverse transcription-polymerase chain reaction and in situ hybridization histochemistry. Results revealed a distinct distribution of LGR8 in forebrain, with transcripts principally restricted to the posterior thalamus and highest densities detected in the parafascicular nucleus of both adult and developing rats. Unexpectedly, INSL3 mRNA was not detected in brain by similar methods, but preliminary electrophysiologic studies of parafascicular neurons revealed that INSL3 altered their activity. These findings suggest that LGR8 signaling may be involved in sensorimotor control in the rat and perhaps other species, particularly via actions on parafascicular neurons that project to basal ganglia and are depleted in Parkinson's disease.
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PMID:Restricted expression of LGR8 in intralaminar thalamic nuclei of rat brain suggests a role in sensorimotor systems. 1595 53

Alpha-synuclein is one of the causative proteins of familial Parkinson disease, which is characterized by neuronal inclusions named Lewy bodies. Lewy bodies include not only alpha-synuclein but also aggregates of other proteins. This fact raises a question as to whether the formation of alpha-synuclein amyloid fibrils in Lewy bodies may occur via interaction with fibrils derived from different proteins. To probe this hypothesis, we investigated in vitro fibril formation of human alpha-synuclein in the presence of preformed fibril seeds of various different proteins. We used three proteins, Escherichia coli chaperonin GroES, hen lysozyme, and bovine insulin, all of which have been shown to form amyloid fibrils. Very surprisingly, the formation of alpha-synuclein amyloid fibril was accelerated markedly in the presence of preformed seeds of GroES, lysozyme, and insulin fibrils. The structural characteristics of the natively unfolded state of alpha-synuclein may allow binding to various protein particles, which in turn triggers the formation (extension) of alpha-synuclein amyloid fibrils. This finding is very important for understanding the molecular mechanism of Parkinson disease and also provides interesting implications into the mechanism of transmissible conformational diseases.
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PMID:Amyloid fibril formation of alpha-synuclein is accelerated by preformed amyloid seeds of other proteins: implications for the mechanism of transmissible conformational diseases. 1616 99

1-Methyl-4-phenylpyridinium ion (MPP+), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome characterized by elevation of intracellular reactive oxygen species level and apoptotic death. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. Adiponectin can also suppress superoxide generation in endothelial cells. In the present study, we investigated the protective effects of adiponectin on MPP+-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Our results suggest that the protective effects of adiponectin on MPP+-induced apoptosis may be ascribed to its anti-oxidative properties, anti-apoptotic activity via inducing expression of SOD and catalase, and regulation of Bcl-2 and Bax expression. These data indicated that adiponectin might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative diseases such as Parkinson's disease.
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PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP+-induced cytotoxicity. 1655 29

1. Human embryonic stem cells (hESC) hold promise for overcoming many diseases because they provide a potential source for many of the slow-growing cell types needed for effective tissue repair, such as the dopaminergic neural cells for Parkinson's disease or the pancreatic islet cells needed to relieve diabetic patients of their daily insulin injections. 2. Human embryonic stem cells can be characterized by several surface antigen markers, transcription factors and enzymes, as well as their ability to differentiate into cells representative of the three germ layers, both in vivo and in vitro. 3. Significant progress has been made in defining the feeder-free and serum-free conditions needed for the culture of hESC. The fibroblast growth factor-2 and transforming growth factor-b signalling pathways appear to be important in maintaining self-renewal and preventing differentiation, respectively. 4. Several important quality controls, including karyotyping, immunogenicity and murine viral assays, will have to be established to monitor the production of hESC for therapeutic purposes. 5. Methods of expansion and differentiation of hESC are still in their infancy and the efficiency of these processes needs to be significantly enhanced.
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PMID:Human embryonic stem cells: technological challenges towards therapy. 1670 Aug 84

Many lines of evidence implicate mitochondria in phenotypic variation: (a) rare mutations in mitochondrial proteins cause metabolic, neurological, and muscular disorders; (b) alterations in oxidative phosphorylation are characteristic of type 2 diabetes, Parkinson disease, Huntington disease, and other diseases; and (c) common missense variants in the mitochondrial genome (mtDNA) have been implicated as having been subject to natural selection for adaptation to cold climates and contributing to "energy deficiency" diseases today. To test the hypothesis that common mtDNA variation influences human physiology and disease, we identified all 144 variants with frequency >1% in Europeans from >900 publicly available European mtDNA sequences and selected 64 tagging single-nucleotide polymorphisms that efficiently capture all common variation (except the hypervariable D-loop). Next, we evaluated the complete set of common mtDNA variants for association with type 2 diabetes in a sample of 3,304 diabetics and 3,304 matched nondiabetic individuals. Association of mtDNA variants with other metabolic traits (body mass index, measures of insulin secretion and action, blood pressure, and cholesterol) was also tested in subsets of this sample. We did not find a significant association of common mtDNA variants with these metabolic phenotypes. Moreover, we failed to identify any physiological effect of alleles that were previously proposed to have been adaptive for energy metabolism in human evolution. More generally, this comprehensive association-testing framework can readily be applied to other diseases for which mitochondrial dysfunction has been implicated.
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PMID:Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. 1730 9

Acetaldehyde, an inhibitor of mitochondrial function, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of the intracellular reactive oxygen species (ROS) level and apoptosis. Adiponectin, secreted from adipose tissue, mediates systemic insulin sensitivity with liver and muscle as target organs. In this study, we investigated the protective effects of adiponectin on acetaldehyde-induced apoptosis in human neuroblastoma SH-SY5Y cells and attempted to examine its mechanism. Acetaldehyde-induced apoptosis was moderately reversed by adiponectin treatment. Our results suggest that the protective effects of adiponectin on acetaldehyde-induced apoptosis may be ascribed to ability to induce the expression of anti-oxidant enzymes and to regulate Bcl-2 and Bax expression. These data indicate that adiponectin may provide a useful therapeutic strategy for the prevention of progressive neurodegenerative disease such as Parkinson's disease.
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PMID:Adiponectin protects human neuroblastoma SH-SY5Y cells against acetaldehyde-induced cytotoxicity. 1681 56

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
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PMID:Molecular misreading: the occurrence of frameshift proteins in different diseases. 1705 86


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