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

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important cellular mechanisms for protein degradation. To investigate the role of autophagy in reversing neuronal injury, the proteasome inhibitor lactacystin was used to cause UPS dysfunction in differentiated PC12 cells and in C57BL/6 mice and rapamycin was used as an autophagy enhancer. The results showed that rapamycin pre-treatment attenuated lactacystin-induced apoptosis and reduced lactacystin-induced ubiquitinated protein aggregation in differentiated PC12 cells. The observed protection was partially blocked by the autophagy inhibitor 3-methyladenine. Furthermore, post-treatment of mice with rapamycin significantly attenuated lactacystin-induced loss of nigral DA neurons and the reduction of striatal DA levels. The lactacystin-induced high molecular ubiquitinated proteins were also attenuated by rapamycin treatment in vivo. In addition, as a chemical compound, rapamycin caused an increase of bcl2 protein level and blocked the release of cytochrome c from mitochondria to cytosal. We concluded that the neuroprotective effect of rapamycin is partially mediated by autophagy enhancement through enhanced degradation of misfolded proteins and autophagy enhancement may be considered to be a promising strategy to prevent diseases associated with misfolded/aggregated proteins, such as Parkinson's disease.
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PMID:Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. 1864 Feb 76

Parkinson disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. It has been proposed that dysfunction of the ubiquitin proteasome system plays an important role in the pathogenesis of Parkinson disease, but the mechanisms underlying ubiquitin proteasome system-related neuron degeneration are unknown. Here, we demonstrate that the proteasome inhibitor lactacystin induces phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, the release of cytochrome c, activation of both caspase-9 and caspase-3, and sequential apoptosis of dopaminergic neurons in vitro. Most of these effects can be attenuated by the JNK inhibitor SP600125. Furthermore, infusion of lactacystin in rats in vivo also leads to phosphorylation of JNK before nigral neuron loss; chronic administration of SP600125 also blocks this loss. These results indicate that JNK is involved in proteasome inhibition-induced dopaminergic neuron degeneration through caspase-3-mediated apoptotic pathways, suggesting that this kinase may be a therapeutic target for the prevention of substantia nigra pars compacta degeneration in Parkinson disease patients.
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PMID:c-Jun N-terminal kinase mediates lactacystin-induced dopamine neuron degeneration. 1880 14

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) caused by an abnormal rate of apoptosis. Endogenous stem cells in the adult mammalian brain indicate an innate potential for regeneration and possible resource for neuroregeneration in PD. We previously showed that guanosine prevents apoptosis even when administered 48 hr after the toxin 1-methyl-4-phenylpyridinium (MPP(+)). Here, we induced parkinsonism in rats with a proteasome inhibitor. Guanosine treatment reduced apoptosis, increased tyrosine hydroxylase-positive dopaminergic neurons and expression of tyrosine hydroxylase in the SNc, increased cellular proliferation in the SNc and subventricular zone, and ameliorated symptoms. Proliferating cells in the subventricular zone were nestin-positive adult neural progenitor/stem cells. Fibroblast growth factor-2-expressing cells were also increased by guanosine. Thus, guanosine protected cells from apoptosis and stimulated "intrinsic" adult progenitor/stem cells to become dopaminergic neurons in rats with proteasome inhibitor-induced PD. The cellular/molecular mechanisms underlying these effects may open new avenues for development of novel therapeutics for PD.
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PMID:Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. 1881 92

Failure of the ubiquitin-proteasome system to degrade abnormal proteins may underlie the accumulation of alpha-synuclein and dopaminergic neuronal degeneration that occurs in Parkinson's disease. Consequently, a reduction of functional proteasome activity has been implicated in Parkinson's disease. VP025 (Vasogen Inc.) is a preparation of phospholipid nanoparticles incorporating phosphatidylglycerol that has been shown to have neuroprotective effects. We show that VP025 prevents the deficits in motor coordination and dopamine observed in a proteasome inhibitor rat model of PD. Thus, VP025 may have a therapeutic effect on the impairment of dopaminergic-mediated motor activity induced by proteasome inhibition.
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PMID:Treatment with phosphotidylglycerol-based nanoparticles prevents motor deficits induced by proteasome inhibition: implications for Parkinson's disease. 1881 14

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

Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
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PMID:Systemic administration of proteasome inhibitor protects against MPTP neurotoxicity in mice. 1937 Apr 11

The involvement of environmental heavy metals in Parkinson's disease (PD) has been suggested by epidemiologic studies; however, the mechanism of this effect is unknown. PD is characterized by the aggregation of alpha-synuclein in Lewy bodies. We previously showed that Pb2+ accelerates proteasomal activity. Therefore, we examined the effect of Pb2+, Ga3+, and Cu2+ on alpha-synuclein in human SH-SY5Y cells. The heavy metals induced an increase in heme-oxygenase-1 levels without significant cell death or ROS generation. The metals inhibited ALA-dehydratase, which is the inhibitory subunit of the proteasome, thereby accelerating proteasomal activity and decreasing protein levels of CDK-1 and PBGD. However, alpha-synuclein protein levels increased after exposure to metals, similar to the effect obtained with the proteasome inhibitor, hemin, suggesting that alpha-synuclein is inaccessible to proteasomal degradation. Indeed, electron microscopy revealed the formation of aggresomes in Pb2+- or hemin-treated cells. Thus, although heavy metals enhance proteasomal activity, alpha-synuclein is protected from degradation, and its protein levels and aggregation are increased.
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PMID:Accelerated proteasomal activity induced by Pb2+, Ga3+, or Cu2+ exposure does not induce degradation of alpha-synuclein. 1939 51

Parkinson's disease is a common neurodegenerative disease in the elderly. Its causes and mechanisms are not clearly understood. To explore the specific role of autophagy and the ubiquitin-proteasome pathway in apoptosis, a specific proteasome inhibitor and macroautophagy inhibitor and stimulator were selected to investigate pheochromocytoma (PC12) cell lines transfected with human mutant (A30P) and wild-type (WT) alpha-synuclein. The apoptosis ratio was assessed by flow cytometry. LC3, heat shock protein 70 (hsp70) and caspase-3 expression in cell culture were determined by Western blot. The hallmarks of apoptosis and autophagy were assessed with transmission electron microscopy. Compared to the control group or the rapamycin (autophagy stimulator) group, the apoptosis ratio in A30P and WT cells was significantly higher after treatment with inhibitors of the proteasome and macroautophagy. The results of Western blots for caspase-3 expression were similar to those of flow cytometry; hsp70 protein was significantly higher in the proteasome inhibitor group than in control, but in the autophagy inhibitor and stimulator groups, hsp70 was similar to control. These findings show that inhibition of the proteasome and autophagy promotes apoptosis, and the macroautophagy stimulator rapamycin reduces the apoptosis ratio. And inhibiting or stimulating autophagy has less impact on hsp70 than the proteasome pathway.
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PMID:Role of autophagy and proteasome degradation pathways in apoptosis of PC12 cells overexpressing human alpha-synuclein. 1942 84

Proteins tagged with lysine (Lys, K) 48 polyubiquitins chains are destined for degradation by the 26S proteasomal system. Impairment of the ubiquitin proteasome system (UPS) function culminates in the accumulation of polyubiquitinated proteins in many neurodegenerative conditions including Parkinson's disease (PD). Nevertheless, the cellular mechanisms underlying cell death induced by an impaired UPS are still not clear. Intriguingly, recent studies indicate that several proteins associated with familial PD are capable of promoting the assembly of Lys-63 polyubiquitin chains. Therefore, the objective of this study was to examine the role of K48 and K63 ubiquitination in mitochondria-mediated apoptosis in in vitro models of dopaminergic degeneration. Exposure of the widely used proteasome inhibitor MG-132 to dopaminergic neuronal cell line (N27) induced a rapid accumulation of polyubiquitinated proteins in the mitochondria. This appears to result in the preferential association of ubiquitin conjugates in the outer membrane and polyubiquitination of outer membrane proteins. Interestingly, the ubiquitin(K48R) mutant effectively rescued cells from MG-132-induced mitochondrial apoptosis without altering the antioxidant status of cells; whereas the ubiquitin(K63R) mutant augmented the proapoptotic effect of MG-132. Herein, we report a novel conclusion that polyubiquitinated proteins, otherwise subjected to proteasomal degradation, preferentially accumulate in the mitochondria during proteolytic stress; and that polyubiquitination of Lys-48 and Lys-63 are key determinants of mitochondria-mediated cell death during proteasomal dysfunction. Together, these findings yield novel insights into a crosstalk between the UPS and mitochondria in dopaminergic neuronal cells.
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PMID:Mitochondrial accumulation of polyubiquitinated proteins and differential regulation of apoptosis by polyubiquitination sites Lys-48 and -63. 1943 18


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