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)

alpha-Synuclein accumulation plays an important role in the pathogenesis of Lewy body disease (LBD) and Parkinson's disease (PD). Although the mechanisms are not yet clear, it is possible that dysregulation of the extracellular signal-regulated kinase (ERK) might play a role. As caveolins form scaffolds onto which signaling molecules such as ERK can assemble, we propose that signaling alterations associated with alpha-synuclein accumulation and neurodegeneration, might be mediated via caveolae. Therefore, the objective of the present study was to investigate the potential contribution of alterations in the caveolar system in mediating alpha-synuclein effects on the ERK signaling pathway. For this, synuclein-transfected B103 neuroblastoma cells were used as a model system. In this cell line, caveolin-1 expression was up-regulated, whereas, ERK was down-regulated. ERK was weakly but consistently co-immunoprecipitated with alpha-synuclein but caveolin-1 did not co-immunoprecipitate with alpha-synuclein. Moreover, treatment of alpha-synuclein- overexpressing cells with caveolin-1 antisense oligonucleotides resulted in stimulation of ERK activity, with amelioration of the neuritic alterations. Transduction of alpha-synuclein-overexpressing cells, with an adenoviral vector directing the expression of ERK, resulted in suppression of caveolin-1 expression and re-establishment of the normal patterns of neurite outgrowth. These results suggest that alpha-synuclein may also interfere with ERK signaling by dysregulating caveolin-1 expression. Thus, the caveolin-1/ERK pathway could be a therapeutic target for the alpha-synuclein-related neurodegenerative disorders.
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PMID:Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease. 1278 66

Parkinson's disease is a neurodegenerative disorder associated with the selective death of dopaminergic neurons. Glial cell line-derived neurotrophic factor (GDNF) can protect dopaminergic neurons in several parkinsonian models. We used the dopaminergic cell line MN9D to explore the mechanisms underlying GDNF-mediated protection against the neurotoxin 6-hydroxydopamine (6-OHDA). MN9D cell viability was decreased 24 hr after a 15-min exposure to 6-OHDA (50-1000 microM) as revealed by staining with Hoechst reagent and Trypan blue. The addition of GDNF (10 ng/ml) before, during, and after exposure to 6-OHDA significantly increased the number of viable cells as assessed by Hoechst staining. In contrast, 6-OHDA-induced cell membrane damage was unaffected as measured by Trypan blue exclusion. The PI3K specific inhibitor LY294002 (10-50 microM) blocked GDNF-mediated protection against nuclear condensation, as did the MAPK kinase (MEK) inhibitor U0126 (5- 20 microM). These studies suggest that GDNF can protect dopaminergic cells against some but not all aspects of 6-OHDA-induced toxicity by acting through both PI3K and MAPK signaling pathways.
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PMID:Effects of GDNF on 6-OHDA-induced death in a dopaminergic cell line: modulation by inhibitors of PI3 kinase and MEK. 1281 14

The present study examined whether thrombin-induced microglial activation could contribute to death of dopaminergic neurons in the rat substantia nigra (SN) in vivo. Seven days after thrombin injection into the SN, tyrosine hydroxylase immunohistochemistry showed a significant loss of nigral dopaminergic neurons. In parallel, thrombin-activated microglia, visualized by immunohistochemical staining using antibodies against the complement receptor type 3 (OX-42) and the major histocompatibility complex class II antigens were also observed in the SN, where degeneration of nigral neurons was found. Reverse transcription PCR at various time points demonstrated that activated microglia in vivo exhibited an early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and several proinflammatory cytokines, including interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor alpha. Western blot analysis and double-label immunohistochemistry showed an increase in the expression of iNOS and COX-2 and the colocalization of these proteins within microglia. The thrombin-induced loss of SN dopaminergic neurons was partially inhibited by NG-nitro-L-arginine methyl ester hydrochloride, an NOS inhibitor, and by DuP-697, a COX-2 inhibitor. Additional studies demonstrated that extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) were activated in the SN as early as 30 min after thrombin injection, and that these kinases were localized within microglia. Inhibition of ERK1/2 and p38 MAPK reduced iNOS and COX-2 mRNA expression and rescued dopaminergic neurons in the SN. The present results strongly suggest that microglial activation triggered by endogenous compound(s) such as thrombin may be involved in the neuropathological processes of dopaminergic neuronal cell death that occur in Parkinson's disease.
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PMID:Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. 1284 92

Free cytoplasmic dopamine may be involved in the genesis of neuronal degeneration in Parkinson's disease and other such diseases. We used SH-SY5Y human neuroblastoma cells to study the effect of dopamine on cell death, activation of stress-induced pathways, and expression of alpha-synuclein, the characteristic protein accumulated in Lewy bodies. We show that 100 and 500 microM dopamine causes a 40% and 60% decrease of viability, respectively, and triggers autophagy after 24 hr of exposure, characterized by the presence of numerous cytoplasmic vacuoles with inclusions. Dopamine causes mitochondrial aggregation in adherent cells prior to the loss of functionality. Plasma membrane and nucleus also maintain their integrity. Cell viability is protected by the dopamine transporter blocker nomifensine and the antioxidants N-acetylcysteine and ascorbic acid. Dopamine activates the stress-response kinases, SAPK/JNK and p38, but not ERK/MAPK or MEK, and increases alpha-synuclein expression. Both cell viability and the increase in alpha-synuclein expression are prevented by antioxidants; by the specific inhibitors of p38 and SAPK/JNK, SB203580 and SP600125, respectively; and by the inhibitor of autophagy 3-methyladenine. This indicates that oxidative stress, stress-activated kinases, and factors involved in autophagy up-regulate alpha-synuclein content. The results show that nonapoptotic death pathways are triggered by dopamine, leading to autophagy. These findings should be taken into account in the search for strategies to protect dopaminergic neurons from degeneration.
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PMID:Dopamine induces autophagic cell death and alpha-synuclein increase in human neuroblastoma SH-SY5Y cells. 1286 68

Given the critical role that the c-Jun N-terminal kinase (JNK) pathway plays in regulating many of the cellular processes which are affected in Parkinson's disease (PD), the possible importance of JNK in disease pathogenesis is being increasingly recognized. Here we review recent findings implicating the JNK signaling pathway in animal models of Parkinson's disease and discuss the relationship between this pathway and the prominent pathological processes observed in the disease state. We suggest that regulation of the JNK signaling pathway may be a central facet in potential treatments for the disease.
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PMID:The role of c-Jun N-terminal kinase (JNK) in Parkinson's disease. 1288 Feb 8

Various stresses cause the accumulation of unfolded proteins in the endoplasmic reticulum (ER). To manage the state, cells have the unfolded protein responses (UPR). If the UPR is unsuccessful, ER-mediated apoptosis occurs. To date, three types of UPR, i.e. the induction of chaperones, the translation block, and ER-associated degradation (ERAD) have been reported. To sense the accumulation of unfolded proteins, the ER has IRE1, PERK, and ATF6. The pathways mediated by IRE1 and ATF6 cause the induction of chaperones. The pathway mediated by PERK causes a translation block. The induction of caspase 12, the activation of the JNK pathway, and the induction of CHOP have been reported as apoptosis caused by ER stress. The stability of the cell is based on the balance between UPR and ER-mediated apoptosis. Recently several diseases have been reported to be related to ER stress. We reported that mutant presenilin 1 causes a vulnerability to ER stress because it attenuates the activation of IRE1, PERK, and ATF6. Recent reports have also shown that Parkinson disease and polyglutamine diseases are relevant to ER stress. Therefore it is suggested that the ER stress story is the common mechanism for neurodegerative disorders.
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PMID:[Involvement of unfolded protein responses in neurodegeneration]. 1288 50

alpha-Synuclein is a presynaptic protein that accumulates abnormally in Lewy bodies of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Its physiological function and role in neuronal death remain poorly understood. Recent immunohistochemical studies suggest that cell cycle-related phenomena may play a role in the pathogenesis of Alzheimer's disease and perhaps other neurodegenerative disorders. In this investigation, we examined the effects of alpha-synuclein expression levels on cell cycle indices in PC12 cells engineered to conditionally induce alpha-synuclein expression upon withdrawal of doxycycline. Over-expression of alpha-synuclein resulted in enhanced proliferation rate and enrichment of cells in the S phase of the cell cycle. This was associated with increased accumulation of the mitotic factor cyclin B and down-regulation of the tumor suppressor retinoblastoma 2. Additionally, ERK1/2, key molecules in proliferation signaling, were highly phosphorylated. Immunohistochemical studies on postmortem brains revealed intense cyclin B immunoreactivity in Lewy bodies in cases with DLB and to a lesser extent in PD. We propose that elevated expression of alpha-synuclein causes changes in cell cycle regulators through ERK activation leading to apoptosis of postmitotic neurons. These changes in cell cycle proteins are also associated with ectopic expression of cyclin B in Lewy bodies.
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PMID:Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. 1288 76

MPTP (1-methyl-1,2,3,6-tetrahydropyridine), a chemical contaminant of synthetic heroin, induces neuropathological changes with clinical features similar to idiopathic Parkinson's disease. The mechanism by which MPTP and its metabolite MPP(+)(1-methyl-4-phenylpyridinium) induces neuronal cell death remains unclear. We employed primary cortical/telencephalon neuronal cultures to investigate the potential role of caspase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) pathways in MPP(+)-induced neuronal death. DNA fragmentation and caspase-3 activity analysis showed that cortical neuronal cells underwent apoptosis after MPP(+)treatment. However, a basal level of apoptotic cells was also observed in untreated cultures. Interestingly, JNK activity increased in untreated cultures over time, whereas it was down-regulated after MPP(+)treatment. This indicates that the JNK pathways could be differentially regulated in different apoptotic processes.
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PMID:Differential regulation of JNK in caspase-3-mediated apoptosis of MPP(+)-treated primary cortical neurons. 1297 83

Rasagiline [N-propargyl-(1R)-aminoindan] a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor exerts neuroprotective and antiapoptotic effects against a variety of insults in cell cultures and in vivo and has finished its phase III clinical trials for Parkinson's disease. In the present study, we show that rasagiline (1 and 10 microM) significantly protected rat PC12 cells against beta-amyloid (Abeta1-42) toxicity. In addition, rasagiline significantly increased (approximately threefold) the secretion of the nonamyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) from SH-SY5Y neuroblastoma and PC12 cells. The increase of sAPPalpha was dose-dependent and was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790 (100 microM), suggesting that the effect is mediated via alpha-secretase activity. Rasagiline-induced sAPPalpha release was significantly reduced by the inhibitors of protein kinase C (PKC), GF109203X, and ERK mitogen-activated protein kinase (MAPK) PD98059. Moreover, rasagiline dose dependently (0.1-10 microM) increased the phosphorylation of p44 and p42 MAPK, which was abolished by PD98059 (30 microM) and GF109203X (2.5 microM). By comparing the actions of rasagiline with those of its S-isomer TVP1022, which is not an MAO inhibitor, we have been able to demonstrate that MAO-B inhibition is not a prerequisite for either sAPPalpha-induced release or ERK phosphorylation. In addition, structure-activity relationship among rasagiline-related compounds suggests the crucial role of the propargyl moiety in these molecules, because propargylamine itself significantly induced the secretion of sAPPalpha and increased MAPK phosphorylation with similar potency to that of rasagiline and its derivatives.
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PMID:The importance of propargylamine moiety in the anti-Parkinson drug rasagiline and its derivatives in MAPK-dependent amyloid precursor protein processing. 1452 44

The anti-Parkinson drug, rasagiline, a irreversible propargyl possessing monoamine oxidase B inhibitor can protect neurons in vitro and in vivo from a variety of neurotoxic insults including SIN-1, glutamate, the parkinsonism inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol and including beta amyloid protein. Recent studies have shown that rasagiline rapidly modulates intracellular signaling pathways involved in cell survival and death. Specifically rasagiline activates Bcl-2, Bcl-xl, protein kinase C (PKC) and reduces Bax in a variety of cells including PC-12 and neuroblastoma human dopamine derived SH-SY5Y cells. These enzymes play key roles in cellular events including modulation of apoptotic processes, neuronal plasticity and amyloid precursor protein processing. This pharmacological action of rasagiline is also associated with the prevention of the neurotoxin induced fall in mitochondrial membrane potential, opening of mitochondria permeability transition pore, activation of proteasome-ubiquitin complex, inhibition of cytochrome c release and prevention of caspase 3 activation, similar to the actions of cyclosporin A or Bcl-2 over expression in SH-SY5Y cells. Rasagiline and its various derivatives induces PKC dependent release of soluble amyloid precursor protein alpha and which is blocked by inhibitors of alpha-secretase, PKC and MAPK-dependent signaling. Structure-activity relationship with various propargyl containing derivatives of rasagiline including propargylamine itself has shown that the above described pharmacological action of these compounds resides in the propargylamine moiety. These results have provided a new understanding into the mechanism of neuroprotective actions of rasagiline and its anti-Alzheimer drug derivatives TV3326 and TV3279, which are relevant for therapy of Parkinson's disease, Alzheimer's disease and other neurodegenerative diseases.
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PMID:The essentiality of Bcl-2, PKC and proteasome-ubiquitin complex activations in the neuroprotective-antiapoptotic action of the anti-Parkinson drug, rasagiline. 1455 44


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