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)

Oxidative stress and apoptosis are considered common mediators of many neurodegenerative disorders including Parkinson's disease (PD). Recently, we identified that PKCdelta, a member of the novel PKC isoform family, is proteolytically activated by caspase-3 to induce apoptosis in experimental models of PD [Eur. J. Neurosci. 18 (6):1387-1401, 2003; Antioxid. Redox Signal. 5 (5):609-620, 2003]. Since caspase-3 cleaves PKCdelta between proline and aspartate residues at the cleavage site 324DIPD327 to activate the kinase, we developed an irreversible and competitive peptide inhibitor, Z-Asp(OMe)-Ile-Pro-Asp(OMe)-FMK (z-DIPD-fmk), to mimic the caspase-3 cleavage site of PKCdelta and tested its efficacy against oxidative stress-induced cell death in PD models. Cotreatment of z-DIPD-fmk with the parkinsonian toxins MPP(+) and 6-OHDA dose dependently attenuated cytotoxicity, caspase-3 activation, and DNA fragmentation in a mesencephalic dopaminergic neuronal cell model (N27 cells). However, z-DIPD-fmk treatment did not block MPP(+)-induced increases in caspase-9 enzyme activity. The z-DIPD-fmk peptide was much more potent (IC50 6 microM) than the most widely used and commercially available caspase-3 inhibitor z-DEVD-fmk (IC50 18 microM). Additionally, z-DIPD-fmk more effectively blocked PKCdelta cleavage and proteolytic activation than the cleavage of another caspase-3 substrate, poly(ADP-ribose) polymerase (PARP). Importantly, the peptide inhibitor z-DIPD-fmk completely rescued TH(+) neurons from MPP(+)- and 6-OHDA-induced toxicity in mouse primary mesencephalic cultures. Collectively, these results demonstrate that the PKCdelta cleavage site is a novel target for development of a neuroprotective therapeutic strategy for PD.
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PMID:A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase C delta (PKCdelta) protects against dopaminergic neuronal degeneration in Parkinson's disease models. 1704 26

Several transgenic mouse lines with altered alpha-synuclein expression have been developed that show a variety of Parkinson's disease-like symptoms without specific loss of dopaminergic neurons. Targeted over-expression of human alpha-synuclein using viral-vector mediated gene delivery into the substantia nigra of rats and non-human primates leads to dopaminergic cell loss and the formation of alpha-synuclein aggregates reminiscent of Lewy bodies. In the context of these recent findings, we used adeno-associated virus (AAV) to over-express wild type human alpha-synuclein in the substantia nigra of mice. We hypothesized that this over-expression would recapitulate pathological hallmarks of Parkinson's disease, creating a mouse model to further characterize the disease pathogenesis. Recombinant AAV expressing alpha-synuclein was stereotaxically injected into the substantia nigra of mice, leading to a 25% reduction of dopaminergic neurons after 24 weeks of transduction. Furthermore, examination of mRNA levels of stress-related proteins using laser capture microdissection and quantitative PCR revealed a positive correlation of Hsp27 expression with the extent of viral transduction at 4 weeks and a positive correlation of Hsp40, Hsp70 and caspase 9 with the extent of viral transduction at 24 weeks. Taken together, our findings suggest that targeted over-expression of alpha-synuclein can induce pathology at the gross anatomical and molecular level in the substantia nigra, providing a mouse model in which upstream changes in Parkinson's disease pathogenesis can be further elucidated.
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PMID:Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. 1724 Nov 27

The neurotoxin 6-hydroxydopamine (6-OHDA) has been widely used to generate an experimental model of Parkinson's disease. It has been reported that reactive oxygen species (ROS), such as the superoxide anion and hydrogen peroxide (H2O2), generated from 6-OHDA are involved in its cytotoxicity; however, the contribution and role of ROS in 6-OHDA-induced cell death have not been fully elucidated. In the present study using PC12 cells, we observed the generation of 50 microM H2O2 from a lethal concentration of 100 microM 6-OHDA within a few minutes, and compared the sole effect of H2O2 with 6-OHDA. Catalase, an H2O2-removing enzyme, completely abolished the cytotoxic effect of H2O2, while a significant but partial protective effect was observed against 6-OHDA. 6-OHDA induced peroxiredoxin oxidation, cytochrome c release, and caspase-3 activation. Catalase exhibited a strong inhibitory effect against the peroxiredoxin oxidation, and cytochrome c release induced by 6-OHDA; however, caspase-3 activation was not effectively inhibited by catalase. On the other hand, 6-OHDA-induced caspase-3 activation was inhibited in the presence of caspase-8, caspase-9, and calpain inhibitors. These results suggest that the H2O2 generated from 6-OHDA plays a pivotal role in 6-OHDA-induced peroxiredoxin oxidation, and cytochrome c release, while H2O2- and cytochrome c-independent caspase activation pathways are involved in 6-OHDA-induced neurotoxicity. These findings may contribute to explain the importance of generated H2O2 and secondary products as a second messenger of 6-OHDA-induced cell death signal linked to Parkinson's disease.
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PMID:Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: involvement of hydrogen peroxide-dependent and -independent action. 1729 91

Dopamine (DA) and its metabolites have been implicated in the pathogenesis of Parkinson's disease. DA can produce reactive-oxygen species and DA-derived quinones such as aminochrome can induce proteasomal inhibition. We therefore examined the ability of DA and MG132 to induce apoptosis and proteasomal inhibition in N27 rat dopaminergic cells. DA (0-500 micromol/L, 0-24 h) and MG132 (0-5 micromol/L, 0-24 h) treated N27 cells resulted in time- and concentration-dependent apoptosis. To better define DA and MG132-induced apoptosis, the activation of initiator caspases 2 and caspase 9 and the executioner caspase 3 was investigated. Activation of caspase 2, caspase 9, and caspase 3 occurred early and prior to cell death. In addition, N-acetylcysteine (NAC) blocked DA but not MG132-induced apoptosis and mitochondrial membrane potential loss. NAC can react with both reactive-oxygen and quinoid metabolites and its inhibitory activity suggests a role for reactive species in DA-induced apoptosis. Proteasomal inhibition was detected after DA treatment in N27 cells which occurred prior to cell death and was abrogated by NAC. Our results implicate DA-derived reactive species in proteasomal inhibition and caspase-dependent apoptosis in N27 cells. The ability of endogenous DA-derived metabolites to induce proteasomal inhibition and apoptosis may contribute to the selective loss of dopaminergic neurons in Parkinson's disease.
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PMID:A comparative study of proteasomal inhibition and apoptosis induced in N27 mesencephalic cells by dopamine and MG132. 1750 67

6-Hydroxydopamine (6-OHDA), a neurotoxin that causes the death of dopamine (DA) neurons, is commonly used to produce experimental models of Parkinson's disease (PD) in rodents. In the rat model of PD first described by Sauer and Oertel, DA neurons progressively die over several weeks following a striatal injection of 6-OHDA. It is generally assumed that DA neurons die through apoptosis after exposure to 6-OHDA, but data supporting activation of a caspase enzymatic cascade are lacking. In this study, we sought to determine if caspases involved in the intrinsic apoptotic cascade play a role in the initial stages of 6-OHDA-induced death of DA neurons in the progressively lesioned rat model of PD. We found that injection of 6-OHDA into adult rat striatum did not activate caspase-9 or caspase-3 or increase levels of caspase-dependent cleavage products in the substantia nigra at various survival times up to 7 days after the lesion, even though this paradigm produced DA neuronal loss. These data suggest that in the adult rat brain DA neurons whose terminals are challenged with 6-OHDA do not die through a classical caspase-dependent apoptotic mechanism.
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PMID:Progressive degeneration of dopamine neurons in 6-hydroxydopamine rat model of Parkinson's disease does not involve activation of caspase-9 and caspase-3. 1778 16

The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.
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PMID:Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. 1789 42

Many studies showed that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was widely used to produce Parkinson's disease (PD)-like models in animals can elicit apoptosis with increase of caspase activity via its neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)). Another pathway shown in MPTP-mediated nigrostriatal dopaminergic cell death involved the c-Jun-N-terminal kinases (JNKs) which are stress-activated protein kinases (SAPKs). Activation of the JNKs leads to the activation of transcription factors such as c-Jun that regulates its own expression. However, it is not known whether the activation of c-Jun is crucial in the stimulation of caspases leading to apoptosis observed in PD-like models. The aim of this study was to investigate the cellular expression and phosphorylation of c-Jun and the caspase-9 activity in rat injured with an intranigral injection of MPP(+). Furthermore, we determined the effects of a cell-permeable peptide TAT-JBD, inhibiting selectively JNKs, on apoptosis markers and on the expression of tyrosine hydroxylase (TH). Our results showed that MPP(+) induced not only an activation of c-Jun but also an early and robust stimulation of caspase-9 in midbrain of rats. Furthermore, a preliminary intravenous injection of TAT-JBD reduced the caspase-9 activation specifically induced by MPP(+) suggesting a control of the JNKs pathway on the intrinsic way of apoptosis in MPP(+)-toxicity. However, the inhibition of the JNK pathway did not prevent TH inhibition, DNA fragmentation and Bad expression in MPP(+)-lesioned substantia nigra of rats. Therefore, the possibility of intervention on the JNK pathway as a therapeutic strategy in Parkinson's disease is questionable.
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PMID:A cell-permeable peptide inhibitor TAT-JBD reduces the MPP+-induced caspase-9 activation but does not prevent the dopaminergic degeneration in substantia nigra of rats. 1803 21

Ropinirole, a D2/D3 receptor agonist has been reported to have neuroprotective effects. We showed that ropinirole can prevent rotenone-induced apoptosis in dopaminergic cell line SH-SY5Y through D3 receptor. We found that ropinirole can block the rotenone-induced phosphorylation of JNK, P38 and p-c-Jun, but promote the phosphorylation of ERK1/2. Furthermore, we demonstrated that ropinirole can reduce the rotenone-induced cleavages of caspase 9, caspase 3 and PARP and elevate the expression of anti-apoptotic proteins of p-Akt and bcl-2. These results provide a basis for neuroprotection by this drug for the treatment of Parkinson disease.
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PMID:D2/D3 receptor agonist ropinirole protects dopaminergic cell line against rotenone-induced apoptosis through inhibition of caspase- and JNK-dependent pathways. 1824 71

The herbicide paraquat is a suspected etiologic factor in the development of Parkinson's disease (PD). Paraquat was therefore used to reproduce Parkinsonian syndromes in lab animals, in which it produces dopaminergic pathogenesis. However, the factors or mechanisms by which paraquat kills dopaminergic neurons are not fully understood. Based on reported evidence that paraquat increases p53 protein levels and inhibits mitochondrial function, it was hypothesized that paraquat induces cell death in dopaminergic neurons through a mechanism in which p53 and mitochondrial apoptotic pathway are linked. To explore this possibility, dopaminergic SY5Y cells were treated with paraquat for 48 h and p53 responses were investigated, as well as biomarkers of the mitochondrial intrinsic pathway of apoptosis. Paraquat significantly increased protein levels of p53 and one of its target genes, Bax. By 24 h, paraquat decreased mitochondrial complex I activity and mitochondrial transmembrane potential and induced the release of cytochrome c from mitochondria. In addition, paraquat increased the activities of caspases 9 and 3. Finally, nuclear condensation and DNA fragmentation occurred 48 h after treatment. The decrease of mitochondrial functions, the release of cytochrome c, the increase of caspase 9 and 3 activities, and DNA damage that were produced by paraquat were inhibited by a specific p53 inhibitor, pifithrin-alpha. These findings support the conclusion that paraquat produced apoptosis in SY5Y cells through the mitochondrial intrinsic pathway associated with p53.
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PMID:Paraquat-induced apoptosis in human neuroblastoma SH-SY5Y cells: involvement of p53 and mitochondria. 1825 95

Emerging evidence implicates impaired protein degradation by the ubiquitin proteasome system (UPS) in Parkinson's disease; however cellular mechanisms underlying dopaminergic degeneration during proteasomal dysfunction are yet to be characterized. In the present study, we identified that the novel PKC isoform PKCdelta plays a central role in mediating apoptotic cell death following UPS dysfunction in dopaminergic neuronal cells. Inhibition of proteasome function by MG-132 in dopaminergic neuronal cell model (N27 cells) rapidly depolarized mitochondria independent of ROS generation to activate the apoptotic cascade involving cytochrome c release, and caspase-9 and caspase-3 activation. PKCdelta was a key downstream effector of caspase-3 because the kinase was proteolytically cleaved by caspase-3 following exposure to proteasome inhibitors MG-132 or lactacystin, resulting in a persistent increase in the kinase activity. Notably MG-132 treatment resulted in translocation of proteolytically cleaved PKCdelta fragments to mitochondria in a time-dependent fashion, and the PKCdelta inhibition effectively blocked the activation of caspase-9 and caspase-3, indicating that the accumulation of the PKCdelta catalytic fragment in the mitochondrial fraction possibly amplifies mitochondria-mediated apoptosis. Overexpression of the kinase active catalytic fragment of PKCdelta (PKCdelta-CF) but not the regulatory fragment (RF), or mitochondria-targeted expression of PKCdelta-CF triggers caspase-3 activation and apoptosis. Furthermore, inhibition of PKCdelta proteolytic cleavage by a caspase-3 cleavage-resistant mutant (PKCdelta-CRM) or suppression of PKCdelta expression by siRNA significantly attenuated MG-132-induced caspase-9 and -3 activation and DNA fragmentation. Collectively, these results demonstrate that proteolytically activated PKCdelta has a significant feedback regulatory role in amplification of the mitochondria-mediated apoptotic cascade during proteasome dysfunction in dopaminergic neuronal cells.
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PMID:Proteasome inhibitor-induced apoptosis is mediated by positive feedback amplification of PKCdelta proteolytic activation and mitochondrial translocation. 1829 51

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