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)

Parkinson's disease (PD) has been proposed to result from a combination of genetic susceptibility and environmental exposure. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in neuron degeneration and in pathogenesis of PD. Nurr1, a member of nuclear receptor superfamily, is a potential susceptibility gene for PD. In this in vitro and in vivo study, we investigated whether Nurr1 deficiency may predispose to environmental proteasome inhibitors-induced neuron injury. We found that lactacystin, an irreversible proteasome inhibitor, caused greater injury to SH-SY5Y cells that Nurr1 expression has been suppressed by small interference RNA (siRNA). On the contrary, the Nurr1 overexpressed SH-SY5Y cells by Nurr1 expression vector transfection rescued the lactacystin-induced injury. In vivo, stereotactic microinjection with lactacystin into right median forebrain bundle (MFB) of mice caused significant inhibition of the proteasome activity in both Nurr1 knock out heterozygous (Nurr1 +/-) mice and their littermate wild-type (Nurr1 +/+) mice. At same time, we found that there was a severer loss of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) and greater reduction of striatal dopamine (DA) levels in Nurr1 +/- mice as compared with that in Nurr1 +/+ mice. Furthermore, lactacystin-induced increase of cleaved PARP, cleaved caspase3 and p53 and decrease of bcl-2 in SN was significantly enhanced in Nurr1 +/- mice. These findings suggest that reduction in Nurr1 expression increases susceptibility to DAergic neuron injury induced by UPS impairment.
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PMID:Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo. 1857 22

On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lectures of M. Racchi on History and future perspectives of Alzheimer Biomarkers and of G. Scapagnini on Cellular Stress Response and Brain Ageing are summarized. Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for clinica dementia. AD prevention is an important goal of ongoing research. Two objectives must be accomplished to make prevention feasible: i) individuals at high risk of AD need to be identified before the earliest symptoms become evident, by which time extensive neurodegeneration has already occurred and intervention to prevent the disease is likely to be less successful and ii) safe and effective interventions need to be developed that lead to a decrease in expression of this pathology. On the whole, data here reviewed strongly suggest that the measurement of conformationally altered p53 in blood cells has a high ability to discriminate AD cases from normal ageing, Parkinson's disease and other dementias. On the other hand, available data on the involvement of curcumin in restoring cellular homeostasis and rebalancing redox equilibrium, suggest that curcumin might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation, such as AD.
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PMID:Alzheimer's disease: new diagnostic and therapeutic tools. 1870 Sep 65

Dopamine-induced neuronal cytotoxicity has been proposed as a leading pathological mechanism underlying many neuronal degenerative disorders including Parkinson disease. Various hypotheses have been proposed including oxidative stress and dopamine (DA)-induced intracellular signal disorder via DA D1 and D2 receptors. The exact mechanism involved in this process is far from clear. In this study, employing a neuronal blastoma cell line, SH-SY5Y, we tried to elucidate the roles of these different suggested mechanisms in this pathological process. The results showed that DA induced cell toxicity in a dose- and time-dependent way. Selective D1 and D2 DA receptor antagonist could not block the cytotoxic effects, whereas reductive reagent ascorbic acid but not GSH could effectively rescue the cell death, suggesting that DA-induced cell toxicity was caused by an extracellular oxidative stress. This was further supported by the enhancing effects of DA transporter blocker, GBR, which could increase the cell death when pretreated. Finally, ascorbic acid could also protect SY5Y cells from DA-induced cellular apoptotic signal changes including PARP and P53. Our studies suggested that DA exerted its cytotoxic effects via an extracellular metabolism, whereas intracellular transportation could reduce its oxidative stress. Cytotoxicity effects induced by extracellular DA could be protected by reductive agents as ascorbic acid. These results help to broaden our understanding of the mechanisms of DA-induced cell death and may provide potentially therapeutical alternative for the neurodegenerative disorders.
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PMID:Extracellular dopamine induces the oxidative toxicity of SH-SY5Y cells. 1872 Apr 20

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Activation of the mixed lineage kinase and c-Jun N-terminal kinase (JNK) has been reported in models of PD. Our focus was to discern whether distinct pathways were activated in cell-specific manner within the SNpc. We now demonstrate the selective phosphorylation of p38 MAP kinase within the dopaminergic neurons, whereas JNK activation occurs predominantly in the microglia. p38 activation results in downstream phosphorylation of p53 and increased p53 mediated transcription of Bax and Puma in the ventral midbrain. Treatment with p38 inhibitor, SB239063 protected primary dopaminergic neurons derived from human progenitor cells from MPP(+) mediated cell death and prevented the downstream phosphorylation of p53 and its translocation to the nucleus in vivo, in the ventral midbrain. The increased staining of phosphorylated p38 in the surviving neurons of SNpc in human brain sections from patients with PD and in MPTP treated mice but not in the ventral tegmental area provides further evidence suggesting a role for p38 in the degeneration of dopaminergic neurons of SNpc. We thus demonstrate the cell specific activation of MAP kinase pathways within the SNpc after MPTP treatment emphasizing the role of multiple signaling cascades in the pathogenesis and progression of the disease. Selective inhibitors of p38 may therefore, help preserve the surviving neurons in PD and slow down the disease progression.
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PMID:Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. 1902 42

Parkinson's disease (PD) is a common neurodegenerative disorder. Neuronal cell death in PD is still poorly understood, despite a wealth of potential pathogenic mechanisms and pathways. Defects in several cellular systems have been implicated as early triggers that start cells down the road toward neuronal death. These include abnormal protein accumulation, particularly of alpha-synuclein; altered protein degradation via multiple pathways; mitochondrial dysfunction; oxidative stress; neuroinflammation; and dysregulated kinase signaling. As dysfunction in these systems mounts, pathways that are more explicitly involved in cell death become recruited. These include JNK signaling, p53 activation, cell cycle re-activation, and signaling through bcl-2 family proteins. Eventually, neurons become overwhelmed and degenerate; however, even the mechanism of final cell death in PD is still unsettled. In this review, we will discuss cell death triggers and effectors that are relevant to PD, highlighting important unresolved issues and implications for the development of neuroprotective therapies.
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PMID:Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps. 1916 1

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important components of cellular mechanisms for protein degradation. In the present study we investigated the functional relationship of the two systems and the interactional role of p53 in vitro. Our study showed that the proteasome inhibitor lactacystin induced an increase in p53 level and autophagy activity, whereas inhibition of p53 by pifithrin-alpha or small interference RNA (siRNA) of p53 attenuated the autophagy induction and increased protein aggregation. Furthermore, we found that pretreatment with the autophagy inhibitor 3-methyladenine or beclin 1 siRNA further activated p53 and its downstream apoptotic pathways, while the autophagy inducer rapamycin showed the opposite effects. Moreover, we demonstrated that rapamycin pretreatment increased tyrosine hydroxylase (TH) protein level in dopamine (DA) neurons, which was associated with its induction of autophagy to degrade aggregated proteins. Our results suggest that p53 can mediate proteasomal inhibition-induced autophagy enhancement which in turn can partially block p53 or its downstream mitochondria-dependent apoptotic pathways. Further autophagy induction with rapamycin protects DA neurons from lactacystin-mediated cell death by downregulating p53 and its related apoptotic pathways and by inducing autophagy to degrade aggregated proteins. Therefore, rapamycin may be a promising drug for protection against neuronal injury relevant to Parkinson disease (PD). Our studies thus provide a mechanistic insight into the functional link between the two protein degradation systems.
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PMID:An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity. 1933 30

Protein p53 is a key player in mitochondrial mediated apoptotic cell death and excess p53 activity has been implicated in many disease states such athrosclerosis, diabetes, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS, P. falciparum and S. typhimurium infections. Thus, chemical inhibitors of p53 activation might prove effective in suppressing diseases associated with excess p53 activity. Diverse chemical compounds are being synthesized and evaluated as potent inhibitors of p53 in many cell types. In this review, we have focused on the effects of apoptosis, which is involved in p53 protein and inhibition of p53 induced apoptosis. Peculiar features of p53 protein and its roles in various diseases are summarized along with important inhibitors developed in recent years.
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PMID:p53-Induced apoptosis and inhibitors of p53. 1960

In Parkinson's disease substantia nigra neurons degenerate likely due to oxidative damage interacting with genetic risk factors. Here, SH-SY5Y cells expressing wild-type or A53T alpha-synuclein had increased sensitivity to methyl-4-phenylpyridinium iodide (MPP(+)), which induces mitochondrial dysfunction, and 6-hydroxydopamine (6-OHDA), which causes oxidative stress. Edaravone protected only against MPP(+), and EGCG ((-)-epigallocatechin-3-O-gallate) protected only against 6-OHDA. Thus genomic responses to MPP(+) and 6-OHDA in the presence of these antioxidants were analyzed using microarrays. Pathway analysis indicated that MPP(+) activated p53 (P < 0.001) while 6-OHDA induced the Nrf2 antioxidative stress response (P < 0.0001). EGCG was more effective at blocking 6-OHDA-mediated genomic responses, while edaravone was more effective against MPP(+). We identified 32 genes that responded to both toxins except in the presence of an effective anti-oxidant; eight are transcription factors and potentially constitute a stress-response transcriptional network. These data provide insights into the mechanisms of neurotoxicity and identifies genes that might mediate antioxidant efficacy.
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PMID:Genome-wide microarray analysis of the differential neuroprotective effects of antioxidants in neuroblastoma cells overexpressing the familial Parkinson's disease alpha-synuclein A53T mutation. 1964 7

DJ-1 was recently identified as a gene product responsible for a subset of familial Parkinson's disease (PD). The mechanisms by which mutations in DJ-1 alter its function and account for PD-related pathology remained largely unknown. We show that DJ-1 is processed by caspase-6 and that the caspase-6-derived C-terminal fragment of DJ-1 fully accounts for associated p53-dependent cell death. In line with the above data, we show that a recently described early-onset PD-associated mutation (D149A) renders DJ-1 resistant to caspase-6 proteolysis and abolishes its protective phenotype. Unlike the D149A mutation, the L166P mutation that prevents DJ-1 dimerization does not impair its proteolysis by caspase-6 although it also abolishes DJ-1 antiapoptotic function. Therefore, we show here that DJ-1 loss of function could be due to impaired caspase-6 proteolysis and we document the fact that various DJ-1 mutations could lead to PD pathology through distinct molecular mechanisms.
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PMID:Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6. 1968 Feb 61

Mutations of the ubiquitin ligase parkin account for most autosomal recessive forms of juvenile Parkinson's disease (AR-JP). Several studies have suggested that parkin possesses DNA-binding and transcriptional activity. We report here that parkin is a p53 transcriptional repressor. First, parkin prevented 6-hydroxydopamine-induced caspase-3 activation in a p53-dependent manner. Concomitantly, parkin reduced p53 expression and activity, an effect abrogated by familial parkin mutations known to either abolish or preserve its ligase activity. ChIP experiments indicate that overexpressed and endogenous parkin interact physically with the p53 promoter and that pathogenic mutations abolish DNA binding to and promoter transactivation of p53. Parkin lowered p53 mRNA levels and repressed p53 promoter transactivation through its Ring1 domain. Conversely, parkin depletion enhanced p53 expression and mRNA levels in fibroblasts and mouse brains, and increased cellular p53 activity and promoter transactivation in cells. Finally, familial parkin missense and deletion mutations enhanced p53 expression in human brains affected by AR-JP. This study reveals a ubiquitin ligase-independent function of parkin in the control of transcription and a functional link between parkin and p53 that is altered by AR-JP mutations.
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PMID:Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. 1980 72


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