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)

Many have hypothesized that cell death in Parkinson's disease is via apoptosis and, specifically, by the mitochondrial-mediated apoptotic pathway. We tested this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, challenged with the Parkinsonism-causing neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion). Apoptosis was the main mode of cell death when the cells were subjected to MPP+ treatment under serum-free conditions for 24 h. Caspase-3 and caspase-9, however, were not activated, thus indicating the existence of alternate or compensatory cell death pathway(s) in dopaminergic neuronal cells. Using caspase inhibitors, we demonstrated that these pathways involve caspase-2, -8, -6 and -7. A time-course study indicated that activation of caspase-2 and -8 occurred upstream of caspase-6 and caspase-7. Upon MPP+ challenge, the apoptosis-inducing factor was translocated from the mitochondria into the MN9D cytosol and nucleus. These results suggest the existence of alternative apoptotic pathways in dopaminergic neurons.
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PMID:Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons. 1566 94

Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations.
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PMID:Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. 1607 29

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

Caspase family has been recognized to be involved in dopaminergic (DA) neuronal death and to exert an unfavorable role in Parkinson's disease (PD) pathology. Our previous study has revealed that caspase-1, as an important component of NLRP3 inflammasome, induces microglia-mediated neuroinflammation in the pathogenesis of PD. However, the role of caspase-1 in DA neuronal degeneration in the onset of PD remains unclear. Here, we showed that caspase-1 knockout ameliorated DA neuronal loss and dyskinesia in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model mice. We further found that caspase-1 knockout decreased MPTP/p-induced caspase-7 cleavage, subsequently inhibited nuclear translocation of poly (ADP-ribose) polymerase 1 (PARP1), and reduced the release of apoptosis-inducing factor (AIF). Consistently, we demonstrated that caspase-1 inhibitor suppressed caspase-7/PARP1/AIF-mediated apoptosis pathway by 1-methyl-4-phenylpyridinium ion (MPP+) stimulation in SH-SY5Y cells. Caspase-7 overexpression reduced the protective effects of caspase-1 inhibitor on SH-SY5Y cell apoptosis. Collectively, our results have revealed that caspase-1 regulates DA neuronal death in the pathogenesis of PD in mice via caspase-7/PARP1/AIF pathway. These findings will shed new insight into the potential of caspase-1 as a target for PD therapy.
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PMID:Caspase-1 Deficiency Alleviates Dopaminergic Neuronal Death via Inhibiting Caspase-7/AIF Pathway in MPTP/p Mouse Model of Parkinson's Disease. 2733 79

Oxidative stress may play critically important roles in the etiology of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a physiological neurotoxin reported to induce oxidative-induced apoptosis of dopaminergic neurons in PD mice models. Valproic acid (VPA), a clinical mood stabilizer, is a HDAC inhibitor with neuroprotective capacities. In the study, we aim at examining the feasibility of VPA as a protector for dopaminergic neurons against damage from 6-OHDA, and the intracellular mechanisms. The 6-OHDA-induced neurotoxicity to the human dopaminergic cell line SH-SY5Y was applied for examining VPA protective effects. Pretreatment with VPA was able to improve cell viability and reduce 6-OHDA-induced reactive oxygen species. Furthermore, a significant suppression of apoptotic caspases including cleaved caspase-3, caspase-7, and caspase-9 was observed. The results also revealed VPA decreased the 6-OHDA-induced Bax/Bcl2 ratio, as measured at protein level. These novel findings indicate that VPA may be capable of protecting the SH-SY5Y dopaminergic neuronal cells from 6-OHDA-induced toxicity via the deceasing of apoptotic caspases (cleaved caspase-3, caspase-7, and caspase-9) and reducing of the Bax/Bcl2 ratio. Very possibly, VPA could serve as not only a mood stabilizer but also a potential antidote for PD prevention.
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PMID:Protective effects of valproic acid on 6-hydroxydopamine-induced neuroinjury. 3216 38

Oxidative stress plays a central role in the common pathophysiology of neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases. Compounds derived from natural sources may offer the potential for new treatment options. Semen Celosiae is a traditional Chinese edible herbal medicine with a long history in China and exhibits wide-reaching biological activities such as hepatoprotective, anti-tumor, anti-diarrheal, anti-diabetic, anti-oxidant, etc. In this study, nine saponins and two phenylacetonitrile glycosides were isolated from Semen Celosiae and their structures were identified using ESI-MS and NMR techniques. Among them, compounds 1 and 2 have not been previously reported. The total concentrations of the five triterpenoid saponins and the two phenylacetonitrile glycosides were 3.348 mg g-1 and 0.187 mg g-1, respectively, suggesting that Semen Celosiae is a novel viable source of the two kinds of compounds. These compounds were observed to significantly attenuate t-BHP-induced neuronal damage by effectively enhancing cell viability and decreasing reactive oxygen species generation and cell apoptosis rate in NSC-34 cells. Furthermore, compounds 1 and 7 reduced the ratios of cleaved caspase-3: caspase-3 and cleaved caspase-7: caspase-7 and the level of cytochrome C, while they increased the levels of SOD1 and Beclin 1. These findings suggest that compounds 1-11 are potent inhibitors of neuron injury elicited by t-BHP, possibly via inhibition of oxidative stress and apoptosis, and activation of autophagy; therefore they may be valuable leads for future therapeutic development.
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PMID:Chemical compounds with a neuroprotective effect from the seeds of Celosia argentea L. 3319 16