Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson disease is the second most frequent neurodegenerative disorder after Alzheimer disease. A subset of genetic forms of Parkinson disease has been attributed to alpha-synuclein, a synaptic protein with remarkable chaperone properties. Synphilin-1 is a cytoplasmic protein that has been identified as a partner of alpha-synuclein (Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M., and Ross, C. A. (1999) Nat. Gen. 22, 110-114), but its function remains totally unknown. We show here for the first time that synphilin-1 displays an antiapoptotic function in the control of cell death. We have established transient and stable transfectants overexpressing wild-type synphilin-1 in human embryonic kidney 293 cells, telecephalon-specific murine 1 neurons, and SH-SY5Y neuroblastoma cells, and we show that both cell systems display lower responsiveness to staurosporine and 6-hydroxydopamine. Thus, synphilin-1 reduces procaspase-3 hydrolysis and thereby caspase-3 activity and decreases poly(ADP-ribose) polymerase cleavage, two main indicators of apoptotic cell death. Furthermore, we establish that synphilin-1 drastically reduces p53 transcriptional activity and expression and lowers p53 promoter transactivation and mRNA levels. Interestingly, we demonstrate that synphilin-1 catabolism is enhanced by staurosporine and blocked by caspase-3 inhibitors. Accordingly, we show by transcription/translation assay that recombinant caspase-3 and, to a lesser extent, caspase-6 but not caspase-7 hydrolyze synphilin-1. Furthermore, we demonstrate that mutated synphilin-1, in which a consensus caspase-3 target sequence has been disrupted, resists proteolysis by cellular and recombinant caspases and displays drastically reduced antiapoptotic phenotype. We further show that the caspase-3-derived C-terminal fragment of synphilin-1 was probably responsible for the antiapoptotic phenotype elicited by the parent wild-type protein. Altogether, our study is the first demonstration that synphilin-1 harbors a protective function that is controlled by the C-terminal fragment generated by its proteolysis by caspase-3.
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PMID:Caspase-3-derived C-terminal product of synphilin-1 displays antiapoptotic function via modulation of the p53-dependent cell death pathway. 1649 29

Mitochondrial dysfunction caused by oxidative stress and genetic defects have been implicated in the loss of dopaminergic neurons in Parkinson's disease. However, the key molecular events that provoke neurodegeneration still remain poorly understood. We recently showed that shortly after exposure to oxidative stress, only those cells showing phosphorylation of p53 at Ser-15 subsequently undergo active cell death. To investigate the role of this early p53 signaling response in cell death, 6-hydroxydopamine was used to induce oxidative stress in dopaminergic neurons generated from embryonic stem cells and PC12-D(2)R cells. Exposure to toxic concentrations of 6-hydroxydopamine induced phosphorylation of p53 at Ser-15 even before cells show mitochondrial permeabilization and apoptosis. We found that 6-hydroxydopamine induced phosphorylation of ataxia telangiectasia mutated (ATM) kinase an event integral to p53 activation and caffeine (ATM kinase inhibitor) inhibited Ser-15 phosphorylation. Phosphorylation of Ser-15 was correlated with enhanced induction and functional activation of p53 manifest as transcription of the pro-apoptotic p53 target Puma. Moreover, inhibition of the p53 abrogated the induction of Puma and promotion of apoptosis due to 6-hydroxydopamine treatments. Thus, these data suggest that activation of p53 signaling immediately after neurotoxin exposure acts as an initiating factor to mediate apoptosis in dopaminergic cells.
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PMID:Activation of p53 signaling initiates apoptotic death in a cellular model of Parkinson's disease. 1654 96

Presence of mutated and/or structurally modified (e.g., denatured, aggregated) protein p53 form is associated with several disorders such as Alzheimer's disease, Parkinson's disease, prion diseases, and many types of tumours. The aim of this work was to distinguish native, denatured and aggregated form of full-length p53 by flow injection analysis coupled with electrochemical detector (FIA-ED). Firstly FIA-ED method used for protein native form determination was optimized (detection limit 45.8 amol per 5 mul injection; 3 x S/N). In addition the technique was applied to identify p53 structural forms (denatured and aggregated). It was found out that denatured form provides about three times higher electrochemical response (protein structure unfolding, approach of more electroactive centers - aminoacid residues - towards electrode surface) in comparison with native form. On the other hand, aggregated form offers lower response (steric eclipse of electroactive protein parts) when compared with the signal of native form. The obtained data show that we are not only able to sensitively determine native, denatured, and aggregated structural forms of p53 protein but also to distinguish them.
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PMID:Change of the protein p53 electrochemical signal according to its structural form - quick and sensitive distinguishing of native, denatured, and aggregated form of the "guardian of the genome". 1672 58

Unlike normal somatic cells, human embryonic stem cells (hESCs) can proliferate indefinitely in culture in an undifferentiated state where they do not appear to undergo senescence and yet remain nontransformed. Cells maintain their pluripotency both in vivo and in vitro, exhibit high telomerase activity, and maintain telomere length after prolonged in vitro culture. Thus, hESCs may provide an unlimited cell source for replacement in a number of aging-related neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease as well as other neurological disorders including spinal cord injuries. The ability of hESCs to bypass senescence is lost as hESCs differentiate into fully differentiated somatic cells. Evidence has been accumulated that differences in telomere length, telomerase activity, cell cycle signaling, DNA repair ability, as well as the lack of genomic, mitochondrial and epigenetic changes, may contribute to the lack of senescence in hESC. In this manuscript, we will review recent advances in characterizing hESCs and monitoring changes in these aspects in prolonged cultures. We will focus on the potential roles of several cellular pathways including the telomerase, p53 and the Rb pathways in escaping senescence in hESCs. We will also discuss the genomic and epigenetic changes in long-term hESC culture and their potential roles in bypassing senescence.
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PMID:Human embryonic stem cells: long term stability, absence of senescence and a potential cell source for neural replacement. 1705 53

Proteasome dysfunction has been demonstrated in Parkinson disease (PD), and proteasome inhibitors have been shown to induce degeneration of dopaminergic neurons in vitro and in vivo. The mechanism whereby proteasome dysfunction leads to dopaminergic cell death, however, is unknown. In this study, we show that proteasome inhibition in both PC12 cells and dopaminergic neurons derived from embryonic stem cells is associated with mitochondrial membrane permeabilization, activation of caspase-3, and nuclear changes consistent with apoptosis. Prior to the emergence of apoptotic features, we found that proteasome inhibition induced increased levels of phosphorylated p53. Inhibition of p53 by pifithrin-alpha or by RNA interference prevented mitochondrial membrane permeabilization and cytotoxicity. There was no increase in p53 mRNA in proteasome-inhibited cells, suggesting that p53 was increased in a transcription-independent manner. Further, there was no increase in Puma or Bax mRNA and p53 co-immunoprecipitated with Bcl-xL and Mdm2. These findings suggest that p53 mediates cell death by way of a direct mitochondrial effect in this model. We also observed increased levels of phosphorylated p53 in dopamine neurons of the substantia nigra pars compacta of mice following systemic administration of a proteasome inhibitor. These changes preceded degeneration of dopaminergic neurons. Increased phosphorylated p53 was also demonstrated in the substantia nigra pars compacta of post-mortem PD brains. These results suggest that abnormalities in p53 signaling play a role in dopaminergic cell death induced by proteasome inhibition and may be relevant to neurodegeneration in PD.
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PMID:p53 mediates nontranscriptional cell death in dopaminergic cells in response to proteasome inhibition. 1706 Mar 22

Mutations in DJ-1 lead to early onset Parkinson's disease (PD). The aim of this study was to elucidate further the underlying mechanisms leading to neuronal cell death in DJ-1 deficiency in vivo and determine whether the observed cell loss could be prevented pharmacologically. Inactivation of DJ-1 in zebrafish, Danio rerio, resulted in loss of dopaminergic neurons after exposure to hydrogen peroxide and the proteasome inhibitor MG132. DJ-1 knockdown by itself already resulted in increased p53 and Bax expression levels prior to toxin exposure without marked neuronal cell death, suggesting subthreshold activation of cell death pathways in DJ-1 deficiency. Proteasome inhibition led to a further increase of p53 and Bax expression with widespread neuronal cell death. Pharmacological p53 inhibition either before or during MG132 exposure in vivo prevented dopaminergic neuronal cell death in both cases. Simultaneous knockdown of DJ-1 and the negative p53 regulator mdm2 led to dopaminergic neuronal cell death even without toxin exposure, further implicating involvement of p53 in DJ-1 deficiency-mediated neuronal cell loss. Our study demonstrates the utility of zebrafish as a new animal model to study PD gene defects and suggests that modulation of downstream mechanisms, such as p53 inhibition, may be of therapeutic benefit.
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PMID:p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. 1716 73

Neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and other neurological disorders remain major problem worldwide since is currently no effective treatment. Thus, studying the mechanisms involved in neuronal apoptotic pathways is imperative if drugs that might stop or delay these disease processes are to be synthesized. In recent years it has become evident that mitochondria are key component of the neuronal apoptotic route. In addition to mitochondria, other intracellular components have been implicated in this process. Thus, DNA damage and re-entry into the cell cycle may constitute a common pathway in apoptosis in neurological diseases. The implication of cell cycle in neurodegenerative disorders is supported by data on the brain of patients who showed an increase in cell cycle protein expression. Indeed, studies performed in neuronal cell preparations indicate that re-entry into the cell cycle and, more specifically, an increase in the expression of E2F-1 transcription role of DNA damage/repair as a potential mechanism in cell cycle re-entry. In this context, ataxia telangiectasia mutated protein could be the enzyme responsible for neuronal apoptosis activation. Furthermore, the potential routes involved in E2F-1 induced apoptosis, p53-dependent and p53-independent, are similarly reviewed. Under this hypothesis, multiple pathways have been suggested, including the route of caspases. Finally, given the increasing experimental data on the neuroprotective and antiapoptotic effects of cyclin dependent kinase CDK inhibitory drugs, including flavopiridol, their application for the treatment of neurological disorders is proposed.
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PMID:Implication of the transcription factor E2F-1 in the modulation of neuronal apoptosis. 1717 8

We and other workers found markedly increased levels of proinflammatory cytokines and apoptosis-related proteins in parkinsonian brain. Although the pathogenesis of Parkinson's disease (PD) remains enigmatic, apoptosis might be involved in the degeneration of dopaminergic neurons in PD. To investigate the possible presence of other inflammatory cytokines and/or apoptosis-related protein, the levels of p53 protein, interferon-gamma, and NF-kappaB were measured for the first time in the brain (substantia nigra, caudate nucleus, putamen, cerebellum, and frontal cortex) from control and parkinsonian patients by a highly sensitive sandwich enzyme-linked immunosorbent assay. The p53 protein level in the caudate nucleus was significantly higher in parkinsonian patients than in controls (P<0.05), whereas this protein in the substantia nigra, putamen, and cerebral cortex showed no significant difference between parkinsonian and control subjects. The interferon-gamma level was significantly higher in the nigrostriatal dopaminergic regions (substantia nigra, caudate nucleus, and putamen) in parkinsonian patients than in the controls (P<0.05), but was not significantly different in the cerebellum or frontal cortex between the two groups. In accordance with previous immunohistochemical analysis, the NF-kappaB level in the nigrostriatal dopaminergic regions was significantly higher in parkinsonian patients than in the controls (P<0.05). These data suggest that the significant increase in the levels of p53 protein, interferon-gamma, and NF-kappaB reflect apoptosis and the inflammatory state in the parkinsonian brain and that their elevation is involved in the degeneration of the nigrostriatal dopaminergic neurons.
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PMID:p53 protein, interferon-gamma, and NF-kappaB levels are elevated in the parkinsonian brain. 1719 47

Sporadic Parkinson's disease (PD) is characterized by progressive death of dopaminergic neurons within the substantia nigra. However, pathological cell death within this nucleus is not uniform. In PD, the lateral tier of the substantia nigra (SNl) degenerates earlier and more severely than the more medial nigral component (SNm). The cause of this brain regional vulnerability remains unknown. We have used DNA oligonucleotide microarrays to compare gene expression profiles from the SNl to those of the SNm in both PD and control cases. Genes expressed more highly in the PD SNl included the cell death gene, p53 effector related to PMP22, the tumour necrosis factor (TNF) receptor gene, TNF receptor superfamily, member 21, and the mitochondrial complex I gene, NADH dehydrogenase (ubiquinone) 1beta subcomplex, 3, 12 kDa (NDUFbeta3). Genes that were more highly expressed in PD SNm included the dopamine cell signalling gene, cyclic adenosine monophosphate-regulated phosphoprotein, 21 kDa, the activated macrophage gene, stabilin 1, and two glutathione peroxidase (GPX) genes, GPX1 and GPX3. Thus, there is increased expression of genes encoding pro-inflammatory cytokines and subunits of the mitochondrial electron transport chain, and there is a decreased expression of several glutathione-related genes in the SNl suggesting a molecular basis for pathoclisis. Importantly, some of the genes that are differentially regulated in the SNl are known to be expressed highly or predominantely in glial cells. These findings support the view that glial cells can be primarily affected in PD emphasizing the importance of using a whole tissue approach when investigating degenerative CNS disease.
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PMID:The medial and lateral substantia nigra in Parkinson's disease: mRNA profiles associated with higher brain tissue vulnerability. 1721 32

To evaluate the contribution of NF-kappaB and the NF-kappaB target gene p53 to nigral dopaminergic neuron degeneration in rodent models of Parkinson's disease, time-course of dopaminergic neuron loss as well as changes in the expression of some NF-kappaB-regulated proapoptotic proteins were assayed after unilateral infusion of 6-hydroxydopamine into rat medial forebrain bundle. Substantial loss of tyrosine hydroxylase immunoreactivity in nigral was observed 24 h after 6-hydroxydopamine treatment. The degenerative processes began 12 h after 6-hydroxydopamine administration as evidenced by a positive silver staining. Apoptotic death of dopaminergic neurons was suggested by the appearance of TUNEL-positive nuclei in substantia nigra and internucleosomal DNA fragmentation as detected by agarose gel electrophoresis. NF-kappaB activation in dopaminergic neurons as revealed by immunohistochemistry and electrophoresis mobility shift assay, began at 12 h after 6-hydroxydopamine administration. Levels of c-Myc and p53 immunoreactivities increased after 6-hydroxydopamine treatment, mainly in dopaminergic neurons as indicated by co-localization with tyrosine hydroxylase immunoreactivity. Blockade of NF-kappaB nuclear translocation with recombinant cell-permeable peptide NF-kappaB SN50 inhibited NF-kappaB nuclear translocation and p53 induction. SN50 and the p53 antagonist pifithrin-alpha significantly reduced nigral dopaminergic neuron degeneration. These results suggest that NF-kappaB activation contributes, at least in part, to oxidative stress-induced degeneration of dopaminergic neurons through a NF-kappaB-dependent p53-signaling pathway.
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PMID:NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. 1736 33


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