UMLS:C0030567 - FACTA Search

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Query: UMLS:C0030567 (Parkinson's disease)
63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.
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PMID:Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. 1613 53

Activated microglia are implicated in the pathogenesis of disease-, trauma- and toxicant-induced damage to the CNS, and strategies to modulate microglial activation are gaining impetus. A novel action of the tetracycline derivative minocycline is the ability to inhibit inflammation and free radical formation, factors that influence microglial activation. Minocycline is therefore being tested as a neuroprotective agent to alleviate CNS damage, although findings so far have yielded mixed results. Here, we showed that administration of a single low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or methamphetamine (METH), a paradigm that causes selective degeneration of striatal dopaminergic nerve terminals without affecting the cell body in substantia nigra, increased the expression of mRNAs encoding microglia-associated factors F4/80, interleukin (IL)-1alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1, CCL2) and tumor necrosis factor (TNF)-alpha. Minocycline treatment attenuated MPTP- or METH-mediated microglial activation, but failed to afford neuroprotection. Lack of neuroprotection was shown to be due to the inability of minocycline to abolish the induction of TNF-alpha and its receptors, thereby failing to modulate TNF signaling. Thus, TNF-alpha appeared to be an obligatory component of dopaminergic neurotoxicity. To address this possibility, we examined the effects of MPTP or METH in mice lacking genes encoding IL-6, CCL2 or TNF receptor (TNFR)1/2. Deficiency of either IL-6 or CCL2 did not alter MPTP neurotoxicity. However, deficiency of both TNFRs protected against the dopaminergic neurotoxicity of MPTP. Taken together, our findings suggest that attenuation of microglial activation is insufficient to modulate neurotoxicity as transient activation of microglia may suffice to initiate neurodegeneration. These findings support the hypothesis that TNF-alpha may play a role in the selective vulnerability of the nigrostriatal pathway associated with dopaminergic neurotoxicity and perhaps Parkinson's disease.
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PMID:Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. 1640 14

Toxin-induced animal models of Parkinson's disease (PD) exhibit many of the same neuroinflammatory changes seen in patients suggesting a role for inflammation in DA neuron loss. Yet, despite this inflammation, the progressive loss of DA neurons that characterizes PD is rarely seen in animals. We infused lipopolysaccharide (LPS) or saline into 7-month-old rats that had been exposed to LPS or saline prenatally and assessed them for DA neuron loss and inflammatory measures (interleukin 1 beta, tumor necrosis factor-alpha, glutathione, and activated microglia) over a period of 84 days to examine the role of pre-existing inflammation in progressive DA neuron loss. LPS infusion into both prenatal treatment groups produced neuroinflammation during the 14 days of LPS infusion that subsequently reverted toward normal over the next 70 days. In animals with pre-existing inflammation (i.e., prenatal LPS), however, the acute changes seen were attenuated, but took much longer to return to normal suggesting a prolonged inflammatory response. These inflammatory changes were consistent with the greater acute DA neuron loss seen in the prenatal saline controls and the progressive DA neuron loss seen only in the animals exposed to LPS prenatally. Interestingly, both prenatal treatment groups exhibited increases in microglia over the entire 84-day course of the study. These data suggest that pre-existing neuroinflammation prolongs the inflammatory response that occurs with a second toxic exposure, which may be responsible for progressive DA neuron loss. This provides further support for the "multiple hit" hypothesis of PD.
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PMID:Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally. 1650 77

Alzheimer's disease (AD) and Parkinson's disease (PD) share several pathological mechanisms. The parallels between amyloid beta (Abeta) in AD and alpha-synuclein in PD have been discussed in several reports. However, studies of the last few years show that Abeta also shares several important characteristics with neuromelanin (NM), whose role in PD is emerging. First, both molecules accumulate with aging, the greatest risk factor for AD and PD. Second, in spite of their different structures, Abeta and NM have similar characteristics that could also lead to neuroprotection. Metals are required to catalyze their formation and they can bind large amounts of these metals, generating stable complexes and thus playing a protective role against metal toxicity. Moreover, they may be able to remove toxic species such as oligopeptides and excess cytosolic dopamine. Third, both Abeta and NM have been implicated in parallel aspects of the neuronal death that underlies AD and PD, respectively. For example, both molecules can activate microglia, inducing release of toxic factors such as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nitric oxide (NO). A careful analysis of these parallel effects of Abeta and NM, including their seemingly paradoxical ability to participate in both cell death and protection, may lead to an improved understanding of the roles of these molecules in neurodegeneration and also provide insights into possible parallels in the pathological mechanisms underlying AD and PD.
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PMID:Amyloid beta and neuromelanin--toxic or protective molecules? The cellular context makes the difference. 1668 9

Accumulating evidences suggest that neuroinflammation is involved in the progressive death of dopaminergic neurons in Parkinson's disease. Several studies have shown that intranigral injection of lipopolysaccharide induces inflammation in the substantia nigra leading to death of tyrosine hydroxylase-positive cells. To better understand how the inflammatory response gives rise to neurotoxicity we induced inflammation in substantia nigra by injecting lipopolysaccharide. The damage of substantia nigra dopaminergic neurons was evaluated by immunohistochemistry, reverse transcription-PCR and Western blot analysis of tyrosine hydroxylase. In parallel, activation of microglial cells, a hallmark of inflammation in CNS, was revealed by immunohistochemistry. Similarly the expression of molecules involved in the inflammatory response and apoptotic pathway was also tested, such as cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), inducible nitric oxide synthase and caspase-11. Tyrosine hydroxylase expression (both mRNA and protein) started to decrease around 3 days post-injection. At the mRNA level, our results showed that the cytokines expression peaked shortly (3-6 h) after lipopolysaccharide injection, followed by the induction of inducible nitric oxide synthase and caspase-11 (14 h). However, inducible nitric oxide synthase protein peaked at 24 h and lasted for 14 days. The lipopolysaccharide-induced loss of substantia nigra dopaminergic neurons was partially inhibited by co-injection of lipopolysaccharide with S-methylisothiourea, an inducible nitric oxide synthase inhibitor. Co-injections of lipopolysaccharide with SB203580, a p38 MAP kinase inhibitor, reduced inducible nitric oxide synthase and caspase-11 mRNA expression, and also rescued dopaminergic neurons in substantia nigra. In summary, this is the first report to describe in vivo the temporal profile of the expression of these inflammatory mediators and proteins involved in dopaminergic neuronal death after intranigral injection of lipopolysaccharide. Moreover data strongly support that lipopolysaccharide-induced dopaminergic cellular death in substantia nigra could be mediated, at least in part, by the p38 signal pathway leading to activation of inducible nitric oxide synthase and caspase-11.
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PMID:Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. 1671 9

Glutamate released by activated microglia induces excitoneurotoxicity and may contribute to neuronal damage in neurodegenerative diseases, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, tumor necrosis factor-alpha (TNF-alpha) secreted from activated microglia may elicit neurodegeneration through caspase-dependent cascades and silencing cell survival signals. However, direct neurotoxicity of TNF-alpha is relatively weak, because TNF-alpha also increases production of neuroprotective factors. Accordingly, it is still controversial how TNF-alpha exerts neurotoxicity in neurodegenerative diseases. Here we have shown that TNF-alpha is the key cytokine that stimulates extensive microglial glutamate release in an autocrine manner by up-regulating glutaminase to cause excitoneurotoxicity. Further, we have demonstrated that the connexin 32 hemichannel of the gap junction is another main source of glutamate release from microglia besides glutamate transporters. Although pharmacological blockade of glutamate receptors is a promising therapeutic candidate for neurodegenerative diseases, the associated perturbation of physiological glutamate signals has severe adverse side effects. The unique mechanism of microglial glutamate release that we describe here is another potential therapeutic target. We rescued neuronal cell death in vitro by using a glutaminase inhibitor or hemichannel blockers to diminish microglial glutamate release without perturbing the physiological glutamate level. These drugs may give us a new therapeutic strategy against neurodegenerative diseases with minimum adverse side effects.
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PMID:Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. 1672 May 74

The role of anti-inflammatory cytokines in Parkinson's disease is not completely understood. In this study, using mesencephalic neuron-glia cultures, we report that both pretreatment and post-treatment of rat mesencephalic neuron-glia cultures with interleukin (IL)-10, a natural immune modulator, reduced lipopolysaccharide (LPS)-induced DA neurotoxicity. The main purpose of this study was to elucidate the molecular mechanism underlying IL-10-elicited neuroprotection. IL-10 significantly inhibited LPS-induced production of tumor necrosis factor-alpha, nitric oxide, and extracellular superoxide in microglia cells. In addition, using reconstituted neuron and glia cell cultures, IL-10 was shown to be neuroprotective only in the presence of microglia. More importantly, IL-10 failed to protect DA neurons in cultures from mice lacking NADPH oxidase (PHOX), a key enzyme for extracellular superoxide production in immune cells, suggesting the critical role of PHOX in IL-10 neuroprotection. This conclusion was further supported by the finding that IL-10 inhibited LPS-induced translocation of the cytosolic subunit of NADPH oxidase p47(phox) to the membrane. When the Janus tyrosine kinase (JAK) 1 signaling pathway was blocked, IL-10 failed to attenuate LPS-induced superoxide production, indicating that the JAK1 signaling cascade mediates the inhibitory effect of IL-10. Together, our results suggest that IL-10 inhibits LPS-induced DA neurotoxicity through the inhibition of PHOX activity in a JAK1-dependent mechanism.
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PMID:Interleukin-10 protects lipopolysaccharide-induced neurotoxicity in primary midbrain cultures by inhibiting the function of NADPH oxidase. 1680 59

The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominant-negative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDA-induced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.
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PMID:Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. 1697 20

Inflammatory events may contribute to the pathogenesis of Parkinson's disease (PD). We conducted a case-control study in a cohort of 369 PD cases and another cohort of 326 ethnically matched controls to investigate the association of tumor necrosis factor-alpha (TNF-alpha) promoter single nucleotide polymorphisms (SNPs) with the risk of PD. The overall genotype distribution at T-1031C and C-857T sites showed significant difference between PD cases and controls (P = 0.0062 and 0.0035, respectively). However, only the more frequent -1031 CC genotype was evidently associated with PD (P = 0.0085, odds ratio: 2.96; 95% CI: 1.38-7.09). Pairwise SNP linkage disequilibrium showed -1031 and -863 sites are in strong linkage disequilibrium (D' = 0.93, Delta(2) = 0.80). Pairwise haplotype analysis among the four sites showed that -1031C-863A may act as a risk haplotype among PD cases (P = 0.0028, odds ratio: 2.18; 95% CI: 1.33-3.69).
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PMID:Tumor necrosis factor-alpha promoter polymorphism is associated with the risk of Parkinson's disease. 1719 53

Mutations in the parkin gene are a major cause of autosomal recessive Parkinson's disease. Here we show that the E3 ubiquitin ligase parkin activates signaling through the IkappaB kinase (IKK)/nuclear factor kappaB (NF-kappaB) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF-kappaB activation by an IkappaB super-repressor or a kinase-inactive IKKbeta interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF-kappaB-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKKgamma/NEMO (NF-kappaB essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF-kappaB pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF-kappaB pathway.
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PMID:Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling. 1731 83

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