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 compound 1-methyl-4-phenylpyridinium (MPP) is a selective inhibitor of mitochondrial complex I, and is widely used in model systems to elicit neurochemical alterations that may be associated with Parkinson's disease. In the present study treatment of human neuroblastoma SH-SY5Y cells with MPP resulted in a time- and concentration-dependent activation of the apoptosis-associated cysteine protease caspase-3, and caused morphological changes characteristic of apoptosis. To test if the activation state of the cell survival-promoting phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway affects MPP-induced caspase-3 activation, PI3K was inhibited with LY294002, or activated with insulin-like growth factor-1. MPP-induced caspase-3 activation was increased by inhibition of PI3K, and decreased by stimulation of PI3K, indicative of anti-apoptotic signaling by the PI3K/Akt pathway. To test if glycogen synthase kinase-3beta (GSK3beta), a pro-apoptotic kinase that is inhibited by Akt, is involved in regulating MPP-induced apoptosis, overexpression of GSK3beta and lithium, a selective inhibitor of GSK3beta, were used to directly alter GSK3beta activity. MPP-induced caspase-3 activity was increased by overexpression of GSK3beta. Conversely, the GSK3beta inhibitor lithium attenuated MPP-induced caspase-3 activation. To test if these regulatory interactions applied to other mitochondrial complex I inhibitors, cells were treated with rotenone. Rotenone-induced activation of caspase-3 was enhanced by inhibition of PI3K or increased GSK3beta activity, and was attenuated by inhibiting GSK3beta with lithium. Overall, these results indicate that inhibition of GSK3beta provides protection against the toxic effects of agents, such as MPP and rotenone, that impair mitochondrial function.
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PMID:Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. 1168 67

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 individuals: odds ratio, 1.64; p = 0.007; (H1/H1 individuals: odds ratio, 0.68; p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
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PMID:GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. 1631 83

To study the role of atypical protein kinase C (aPKC) in neurodegenerative disease, we investigated the distribution of PKCiota/lambda, an aPKC isoform, in a variety of tauopathies and alpha-synucleinopathies. Immunohistochemical study revealed PKCiota/lambda within tau-positive neurofibrillary inclusions in Alzheimer disease (AD), progressive supranuclear palsy, corticobasal degeneration (CBD), and Pick disease (PiD), within alpha-synuclein-positive Lewy bodies in idiopathic Parkinson disease and dementia with Lewy bodies, as well as within glial inclusions in multisystem atrophy. We also observed PKCiota/lambda label of actin-rich Hirano bodies in AD, PiD, and elderly individuals. Double immunolabeling and fluorescence resonance energy transfer demonstrated close physical association between PKCiota/lambda and phospho-tau or alpha-synuclein in some neurofibrillary tangles and Lewy bodies. Furthermore, PKCiota/lambda colocalized with p62, a chaperone protein that binds to both aPKC and ubiquitin, in most of these inclusions. PKCiota/lambda also closely associated with the inactivated form of glycogen synthase kinase-3beta, GSK-3beta[ser9]. Together, these findings suggest that PKCiota/lambda may play a role in common mechanisms involving the pathogenesis of neurodegenerative disease.
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PMID:Atypical protein kinase C in neurodegenerative disease II: PKCiota/lambda in tauopathies and alpha-synucleinopathies. 1669 Nov 14

Research by Klein and co-workers suggests that the inhibition of GSK-3beta by small molecules may offer an important strategy in the treatment of a number of central nervous system (CNS) disorders including Alzheimer's disease, Parkinson's disease, and bipolar disorders. Based on results from kinase-screening assays that identified a staurosporine analogue as a modest inhibitor of GSK-3beta, a series of 3-indolyl-4-indazolylmaleimides was prepared for study in both enzymatic and cell-based assays. Most strikingly, whereas we identified ligands having poor to high potency for GSK-3beta inhibition, only ligands with a Ki value of less than 8 nM, namely maleimides 18 and 22, were found to inhibit Tau phosphorylation at a GSK-3beta-specific site (Ser 396/404). Accordingly, maleimides 18 and 22 may protect neuronal cells against cell death by decreasing the level of alpha-Syn protein expression. We conclude that the GSK-3beta inhibitors described herein offer promise in defending cells against MPP+-induced neurotoxicity and that such compounds will be valuable to explore in animal models of Parkinson's disease as well as in other Tau-related neurodegenerative disease states.
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PMID:Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson's disease. 1689 58

Dopaminergic (DA) neurons in the ventral midbrain (VM) are one of the major cell types lost in Parkinson's disease (PD). Proof of principle exists for cell replacement therapies for PD, but wider application is halted by the unavailability of abundant sources of DA neurons. Stem cells might constitute one of these sources. However, efficient protocols promoting their specific differentiation into a DA neuronal phenotype are required. In this review, we summarize the latest findings concerning the contribution of the Wnt family of glycolipoproteins in the development of VM DA neurons. Regulators of Wnt signaling are involved in several neurodevelopmental processes. Recent results indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and different Wnts have specific and unique activity profiles. Interestingly, chemical inhibitors of glycogen synthase kinase-3beta stabilize beta-catenin and increase DA differentiation in VM precursor cultures. We hereby propose that Wnts are likely to contribute in the future to improve stem/precursor cell replacement therapy approaches to PD.
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PMID:Function of Wnts in dopaminergic neuron development. 1690 30

For over fifty years lithium has been a fundamental component of therapy for patients with bipolar disorders. Lithium has been considered recently for its potential to alleviate neuronal loss and other neurodegeneration processes. For instance, lithium reduces the severity of some behavioral complications of Alzheimer's disease (AD). And there are growing indications that lithium may be of benefit to the underlying pathology of AD, as well as an array of other common CNS disorders, including stroke, Parkinson's disease, and Huntington's disease. Despite these demonstrated and prospective therapeutic benefits, lithium's mechanism of action remains elusive, and opinions differ regarding the most relevant molecular targets. Lithium inhibits several enzymes; significant among these are inositol monophosphatase (IMPase), glycogen synthase kinase-3 (GSK-3), and the proteasome. Most recent publications discussing the medical application of lithium have converged on GSK-3, so this article reviews data and discussions regarding the roles and interactions of GSK-3 with other proteins and its proposed role in the pathogenesis of Alzheimer's disease.
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PMID:Glycogen synthase kinase-3 in neurodegeneration and neuroprotection: lessons from lithium. 1731 63

Apoptosis is a contributing cause of dopaminergic neuron loss in Parkinson disease. Recent work has shown that erythropoietin (EPO) offers protection against apoptosis in a wide variety of tissues. We demonstrate that exposure of PC12 cells to 1-methyl-4-phenylpyridinium ion (MPP(+)) with recombinant human EPO, significantly decreased apoptosis as measured by TUNEL and caspase-3 activity when compared to MPP(+) treatment alone. EPO induced sustained phosphorylation of Akt and its substrate, GSK-3beta, reduced caspase-3 activities in PC12 cells. The anti-apoptotic effect of EPO was abrogated by co-treatment with LY294002, the specific blocker of phosphatidylinositol 3-kinase (PI3K). The effects of EPO on GSK-3beta and caspase-3 activities were also blocked by LY294002. LiCl, the inhibitor of GSK-3beta, downregulated the caspase-3 activity and blocked the apoptosis induced by MPP(+). Finally, we determined that EPO transiently activated the ERK signaling pathway, but PD98059, a specific inhibitor of ERK, does not alter the survival effect of EPO in this model system. Thus, these findings indicate that EPO protects against apoptosis in PC12 cells exposed to MPP(+), through the Akt/GSK-3beta/caspase-3 signaling pathway, but the ERK pathway is not involved in the EPO-dependent survival enhancing effect in this model system.
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PMID:Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. 1750 73

Glycogen synthase kinase-3beta (GSK-3beta) is closely involved in neuronal apoptosis and pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease. However, whether GSK-3beta mediates apoptosis of dopaminergic neurons in Parkinson's disease remains elusive. In this study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism models, we investigated whether MPTP induces apoptosis of dopaminergic neurons through a GSK-3beta-dependent pathway. MPTP caused a rapid activation of GSK-3beta, evidenced by the decrease in level of phospho-Ser9 of GSK-3beta and the increase in level of phospho-Ser396 of tau, a known GSK-3beta substrate. Blockage of GSK-3beta activity by its two specific inhibitors, indirubin-3'-oxime and AR-A014418, prevented dopaminergic neurons from MPTP-induced apoptosis. Additionally, inhibition of GSK-3beta activity restored the depletion of striatal dopamine and ameliorated behavioral impairments caused by MPTP. These results indicate that GSK-3beta is a critical intermediate of MPTP neurotoxicity, and inhibition of GSK-3beta may provide a novel strategy to treat Parkinson's disease.
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PMID:Inhibition of glycogen synthase kinase-3beta protects dopaminergic neurons from MPTP toxicity. 1751 24

Drugs targeting the histamine H(3) receptor (H(3)R) are suggested to be beneficial for the treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. The H(3)R activates G(i/o)-proteins to inhibit adenylyl cyclase activity and modulates phospholipase A(2) and MAPK activity. Herein we show that, in transfected SK-N-MC cells, the H(3)R modulates the activity of the Akt/Glycogen synthase kinase 3beta (GSK-3beta) axis both in a constitutive and agonist-dependent fashion. H(3)R stimulation with the H(3)R agonist immepip induces the phosphorylation of both Ser473 and Thr308 on Akt, a serine/threonine kinase that is important for neuronal development and function. The H(3)R-mediated activation of Akt can be inhibited by the H(3)R inverse agonist thioperamide, and by Wortmannin, LY294002 and PTX, suggesting the observed Akt activation occurs via a G(i/o)-mediated activation of phosphoinositide-3-kinase. H(3)R activation also results in the phosphorylation of Ser9 on GSK-3beta, which acts downstream of Akt and has a prominent role in brain function. In addition, we show the H(3)R-mediated phosphorylation of Akt at Ser473 to occur in primary rat cortical neurons and in rat brain slices. The discovery of this signaling property of the H(3)R adds new understanding to the roles of histamine and the H(3)R in brain function and pathology.
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PMID:The Akt/GSK-3beta axis as a new signaling pathway of the histamine H(3) receptor. 1762 45

3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959), a selective agonist for the putative phosphatidylinositol (PI)-linked dopamine receptor (DAR), has been shown to possess potent anti-Parkinson disease effects but produces less dyskinesia and motor fluctuation that are frequently observed in Parkinson disease drug therapies. The present study was designed to detect the neuroprotection of SKF83959 and its potential mechanism for the effect in cultured rat cortical cells. The presence of SKF83959 with a dose range of 0.1-30 micromol/L improved H2O2-reduced cell viability in a dose-dependent manner. The anti-apoptotic action of SKF83959 was partially abolished by pre-application of the D1 antagonist SCH23390 (30 micromol/L) and the PI 3-kinase (PI 3-K) inhibitor LY294002 but not by the MEK1/2 inhibitor PD98059 (30 micromol/L). Moreover, SKF83959 treatment significantly inhibited H2O2-activated glycogen synthase kinase-3beta (GSK-3beta) which was associated with the drug's neuroprotective effect, but this inhibition was attenuated by SCH23390 and a selective PI 3-K inhibitor. Moreover, the application of either SKF83959 or a pharmacological inhibitor of GSK-3beta attenuated the inhibition by H2O2 on the expression of inducible NO synthase and production of NO. This indicates that D1-like receptor, presumably PI-linked D1 receptor, -mediated alteration of PI 3-K/Akt/GSK-3beta pathway is involved in the neuroprotection by SKF83959. In addition, SKF83959 also effectively decreased the level of the lipid peroxidation and increased the activity of GSH-peroxidase altered by H2O2. These results suggest that SKF83959 exerts its neuroprotective effect through both receptor-dependent and independent mechanisms: Inhibition of GSK-3beta and consequently increasing the expression of inducible NO synthase via putative PI-linked DAR; and its anti-oxidative activity which is independent of DAR.
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PMID:Neuroprotective effects of atypical D1 receptor agonist SKF83959 are mediated via D1 receptor-dependent inhibition of glycogen synthase kinase-3 beta and a receptor-independent anti-oxidative action. 1800 41


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