Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 accumulation of misfolded and unfolded proteins in endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). Recent evidence has suggested the relationship between UPR and dopaminergic neuronal cell death in Parkinson's disease (PD); however, it remains unclear whether it makes sense to modulate UPR, to mitigate the progression of PD. In this study, we investigated a role of the IRE1 alpha-XBP1 pathway in the survival of dopaminergic cells, under stress induced by PD-related insults. The exogenous expression of the active-form XBP1 (XBP1s) protein had protective effects against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and proteasome inhibitors. Moreover, adenoviral XBP1s expression significantly suppressed the degeneration of dopaminergic neurons in the mouse model of PD, as induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results demonstrate that the enhancement of XBP1 could be a novel PD therapeutic strategy.
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PMID:Protective effect against Parkinson's disease-related insults through the activation of XBP1. 1913 31

Alpha-synuclein (alphaSyn) is a small cytosolic protein of unknown function, which is highly enriched in the brain. It is genetically linked to Parkinson's disease (PD) in that missense mutations or multiplication of the gene encoding alphaSyn causes early onset familial PD. Furthermore, the neuropathological hallmarks of both sporadic and familial PD, Lewy bodies and Lewy neurites, contain insoluble aggregates of alphaSyn. Several studies have reported evidence that alphaSyn can inhibit phospholipase D (PLD), which hydrolyzes phosphatidylcholine to form phosphatidic acid and choline. Although various hypotheses exist regarding the roles of alphaSyn in health and disease, no other specific biochemical function for this protein has been reported to date. Because PLD inhibition could represent an important function of alphaSyn, we sought to extend existing reports on this interaction. Using purified proteins, we tested the ability of alphaSyn to inhibit PLD activity in cell-free assays. We also examined several cell lines and transfection conditions to assess whether alphaSyn inhibits endogenous or overexpressed PLD in cultured mammalian cells. In yeast, we extended our previous report of an interaction between alphaSyn and PLD-dependent phenotypes, for which PLD activity is absolutely necessary. Despite testing a range of experimental conditions, including those previously published, we observed no significant inhibition of PLD by alphaSyn in any of these systems. We propose that the previously reported effects of alphaSyn on PLD activity could be due to increased endoplasmic reticulum-related stress associated with alphaSyn overexpression in cells, but are not likely due to a specific and direct interaction between alphaSyn and PLD.
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PMID:Evidence that alpha-synuclein does not inhibit phospholipase D. 1914 88

Neurodegenerative disorders are often characterized by the aggregation and accumulation of misfolded proteins (e.g. Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis). Aggregated proteins are very toxic to cells in culture and both in vitro and in vivo there is overwhelming evidence that these aberrant proteins are key players in neurodegeneration. Protein quality control is a cellular defense mechanism against misfolded proteins that prevents aggregate formation under physiological conditions. The presence of accumulated aggregates of misfolded proteins in many neurodegenerative disorders, suggests that protein quality control failed to restore homeostasis in these pathological conditions. In fact, evidence from observations in cellular disease models, mouse models, as well as from post mortem patient material indicates activation of the quality control machinery in response to the pathological process. In addition, interference with protein quality control by genetic or chemical manipulation often results in aggregate formation and neurodegeneration. This stresses the importance of proper quality control in neurodegenerative disorders and indicates that it may provide a target for therapeutic intervention. In this review we will focus on the protein quality control systems in the endoplasmic reticulum (ER) and address the involvement of ER quality control in neurodegenerative disease as well as its potential as therapeutic target.
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PMID:Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy. 1919 26

The orphan G-protein-coupled receptor 37 (GPR37) is a substrate of parkin, and its insoluble aggregates accumulate in brain tissue samples of Parkinson's disease patients, including Lewy bodies and neurites. Parkin activates the clearance of the unfolded receptor, while the overexpression of GPR37, in the absence of parkin, can lead to unfolded protein-induced cell death. We found that overexpression of the human GPR37 receptor in HEK293 cells and consequent activation of an endoplasmic reticulum (ER) stress response had effects comparable to starvation, in inducing the cellular autophagic pathway. Treatment with specific modulators provided further evidence for the autophagic clearance of the overexpressed GPR37 protein, in detergent-soluble and -insoluble fractions, as confirmed by the conversion of the microtubule-associated protein 1, light chain 3 (LC3)-I marker to its LC3-II isoform. Furthermore, Gpr37-null mutant mice displayed consistent alterations of ER stress and autophagic pathway markers in brain tissue samples. These findings show that GPR37 overexpression per se can induce cellular autophagy, which may prevent the selective degeneration of GPR37-expressing neurons, as reported for Parkinson's and related neurodegenerative diseases.
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PMID:Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor. 1921 98

Mutations in two genes encoding the putative kinases LRRK2 and PINK1 have been associated with inherited variants of Parkinson disease. The physiological role of both proteins is not known at present, but studies in model organisms have linked their mutants to distinct aspects of mitochondrial dysfunction, increased vulnerability to oxidative and endoplasmic reticulum stress, and intracellular protein sorting. Here, we show that a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons. We demonstrate that in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-of-function mutants were suppressed. Conversely, the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background. These results provide the first evidence of an antagonistic role of PINK-1 and LRK-1. Due to the similarity of the C. elegans proteins to human LRRK2 and PINK1, we suggest a common role of both factors in cellular functions including stress response and regulation of neurite outgrowth. This study might help to link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes resulting from Parkinson disease-related mutants in both genes, the first manifestations of which are cytoskeletal defects in affected neurons.
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PMID:Caenorhabditits elegans LRK-1 and PINK-1 act antagonistically in stress response and neurite outgrowth. 1925 2

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1(M)) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1(M) in transfected cells is shown to correlate with the intracellular level of alpha-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1(M) in cell culture models of alpha-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces alpha-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1(M), suggesting that it may negatively regulate the lysosomal degradation of alpha-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.
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PMID:Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease. 1926 53

Parkinson's disease (PD) is a common neurodegenerative disorder of which the core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Recent work has revealed that the engagement of L-type Ca(2+) channels during autonomous pacemaking renders SNc DA neurons susceptible to mitochondrial toxins used to create animal models of PD, indicating that homeostatic Ca(2+) stress could be a determinant of their selective vulnerability. This view is buttressed by the central role of mitochondria and the endoplasmic reticulum (linchpins of current theories about the origins of PD) in Ca(2+) homeostasis. Here, we summarize this evidence and suggest the dual roles had by these organelles could compromise their function, leading to accelerated aging of SNc DA neurons, particularly in the face of genetic or environmental stress. We conclude with a discussion of potential therapeutic strategies for slowing the progression of PD.
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PMID:Calcium homeostasis, selective vulnerability and Parkinson's disease. 1930 31

Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Many cellular mechanisms are thought to be involved in the death of these specific neurons in PD, including oxidative stress, changes of intracellular calcium homeostasis, and mitochondrial dysfunction. Since recent studies have revealed that also endoplasmic reticulum (ER) stress in conjunction with abnormal protein degradation can contribute to the PD pathophysiology, we investigated here the molecular mechanisms underlying the interplay between ER and mitochondria and its relevance in the control of neuronal cell death in PD. We observed that MPP+ induced changes in the mitochondrial function, affecting mitochondrial membrane potential and electron transport chain function. Likewise, it was also evident the unfolded protein response activation by an overexpression of GRP78 protein. Moreover, stress stimuli caused the release of Ca2+ from the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. Besides, Ca2+ release inhibition prevented MPP+ mediated mitochondria-dependent caspases activation. Our findings show that ER and mitochondria are in a close communication, establishing a dynamic ER-Ca2+-mitochondria interconnection that can play a prominent role in the neuronal cell death induction under particular stressful circumstances of PD pathology.
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PMID:Endoplasmic reticulum and mitochondria interplay mediates apoptotic cell death: relevance to Parkinson's disease. 1937 64

The endoplasmic reticulum (ER) is a principal site for protein synthesis, protein folding, calcium storage, and calcium signaling. Thapsigargin (TG), an inducer of ER stress, inhibits ER-associated Ca(2+)-ATPase and disrupts Ca(2+) homeostasis. ER stress plays an important pathogenetic role in Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, and prion protein diseases. This study was conducted to evaluate the protective mechanisms of Scrophularia ningpoensis (SN) extracts and chemicals on TG-stimulated U-87MG cells. In this study, the recovery activities of E-harpagoside (EHA), harpagide (HA), 8-O-E-p-methoxycinnamoylharpagide (MH), aucubin (AB), cinnamic acid (CA), p-coumaric acid (pCA), p-methoxycinnamic acid methyl ester (MME), caffeic acid (CFA), ferulic acid (FA), and (E)-p-methoxycinnamic acid (MA) on TG-stimulated U-87MG cells were evaluated. The results revealed that SN, MME, CFA, and MH showed considerable recovery effects. Therefore, SN, MME, CFA, and MH were selected to evaluate the gene expression profile of U-87MG cells by using microarray analysis and real-time RT-PCR. The results of this analysis revealed that cell cycle, proliferation, protein folding, and anti-apoptosis-related genes were up-regulated in SN, MME, CFA, and MH-treated U-87MG cells. In addition, significant decreases in apoptosis, the MAPK signaling pathway, and mitochondria-related gene expressions were observed in SN-, MME-, CFA-, and MH-treated U-87MG cells. Thus, SN, MME, CFA, and MH might affect neurodegenerative diseases.
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PMID:The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. 1944 20

The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca(2+) homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca(2+) regulatory proteins and cause uncontrolled Ca(2+) release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca(2+) homeostasis and ER stress. Here we showed that knockdown of Herp, an ubiquitin-like domain containing ER stress protein, renders PC12 and MN9D cells vulnerable to 1-methyl-4-phenylpyridinium-induced cytotoxic cell death by a mechanism involving up-regulation of CHOP expression and ER Ca(2+) depletion. Conversely, Herp overexpression confers protection by blocking 1-methyl-4-phenylpyridinium-induced CHOP up-regulation, ER Ca(2+) store depletion, and mitochondrial Ca(2+) accumulation in a manner dependent on a functional ubiquitin-proteasomal protein degradation pathway. Deletion of the ubiquitin-like domain of Herp or treatment with a proteasomal inhibitor abolished the central function of Herp in ER Ca(2+) homeostasis. Thus, elucidating the underlying molecular mechanism(s) whereby Herp counteracts Ca(2+) disturbances will provide insights into the molecular cascade of cell death in dopaminergic neurons and may uncover novel therapeutic strategies to prevent and ameliorate Parkinson disease progression.
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PMID:The homocysteine-inducible endoplasmic reticulum stress protein counteracts calcium store depletion and induction of CCAAT enhancer-binding protein homologous protein in a neurotoxin model of Parkinson disease. 1944 87


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