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)

A number of studies have associated the S18Y polymorphic variant of UCH-L1 with protection from sporadic Parkinson's Disease (PD). The mechanism involved in this protective function is unknown, but has generally been assumed to be linked to the ubiquitin-proteasome system (UPS). In the current study, we have investigated the effects of overexpression of UCH-L1 and its variants, including S18Y, in neuronal cells. We find that S18Y, but not WT, UCH-L1 confers a specific antioxidant protective function when expressed at physiological levels in human neuroblastoma cells and primary cortical neurons. In contrast, neither WT nor S18Y UCH-L1 appear to directly impact the proteasome, although they both lead to stabilization of free ubiquitin. Lack of WT mouse UCH-L1 in neurons derived from gad mice led to a decrease of free ubiquitin, but no overall decrease in UPS function or enhanced sensitivity to oxidative stress. We conclude that the S18Y variant of UCH-L1 confers a novel antioxidant function that is not present in the WT form and that this function may underlie the protective effects of this variant in certain PD populations. Our results furthermore provide indirect evidence for the importance of oxidative stress as a pathogenetic factor in certain forms of sporadic PD.
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PMID:The S18Y polymorphic variant of UCH-L1 confers an antioxidant function to neuronal cells. 1841 Dec 55

At the neuropathological level, Parkinson's disease (PD) is characterized by the accumulation of misfolded proteins, which can trigger the unfolded protein response (UPR). UCH-L1 is a component of ubiquitin proteasome system (UPS). It is reported that the loss of its function will impair ubiquitin proteasome system and cause toxicity to cells. But its mechanism has not been illustrated. In this study, we detected the protein expression of Bip/Grp78 and the spliced form of XBP-1 to examine the activation of unfolded protein response after SK-N-SH cells being treated with LDN-57444, a UCH-L1 inhibitor which could inhibit UCH-L1 hydrolase activity. Our data showed that UCH-L1 inhibitor was able to cause cell death through the apoptosis pathway by decreasing the activity of ubiquitin proteasome system and increasing the levels of highly ubiquitinated proteins, both of which can activate unfolded protein response. There is a lot of evidence that unfolded protein response is activated as a protective response at the early stage of the stress; this protective response can switch to a pro-apoptotic response when the stress persists. In this study, we demonstrated this switch by detecting the upregulation of CHOP/Gadd153. Taken together, our data indicated that the apoptosis induced by UCH-L1 inhibitor may be triggered by the activation of endoplasmic reticulum stress (ERS). Moreover, we provide a new cell model for studying the roles of UCH-L1 in Parkinson's disease.
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PMID:Endoplasmic reticulum stress contributes to the cell death induced by UCH-L1 inhibitor. 1862 88

Mutation in UCH-L1 has been reported as a rare cause of autosomal dominant Parkinson's disease (PD). A S18Y polymorphism in the same gene has been associated with sporadic PD. We investigated the frequency of this polymorphism among the Han-Chinese ethnic population in a case-control study. A total of 600 patients with PD and 334 unrelated healthy controls were genotyped using PCR-restriction fragment length polymorphism analysis. We did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05). Our results do not support a role for this variant in sporadic PD.
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PMID:Lack of evidence for association of a UCH-L1 S18Y polymorphism with Parkinson's disease in a Han-Chinese population. 1863 28

In the case of Parkinson's disease (PD), classical animal models have utilized dopaminergic neurotoxins such as 6-hydroxydopamine (6OHDA) and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). More recently, human genetic linkage studies have identified several genes in familial forms of PD. Transgenic models have been made that explore the function of PD-linked genes (e.g. alpha-synuclein, DJ-1, LRRK2, Parkin, UCH-L1, PINK1). Recent evidence suggests mitochondrial dysfunction may play a major role in PD. Manipulation of mitochondrial respiratory genes (e.g. mitochondrial transcription factor A or TFAM) also elicits a PD phenotype in mice. Transgenic mice (MitoPark) were developed that have TFAM selectively knocked out in dopaminergic neurons. The nigral dopamine neurons of MitoPark mice show respiratory chain dysfunction, accompanied by the development of intraneuronal inclusions and eventual cell death. In early adulthood, the MitoPark mice show a slowly progressing loss of motor function that accompanies these cellular changes. The MitoPark mouse enables further study of the role of mitochondrial dysfunction in DA neurons as an important mechanism in the development of PD. Transgenic technology has allowed new insights into mechanisms of neurodegeneration for a number of neurological disorders. This paper will summarize recent studies on several transgenic models of PD.
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PMID:Transgenic rodent models of Parkinson's disease. 1864 40

Parkinson's disease (PD) results from the death of specific neuronal populations in the CNS. Potential causative factors include environmental toxins and gene mutations that can combine to dysregulate the processing and degradation of alpha-synuclein. Oxidative stress induced by the neurotoxins MPTP, paraquat, maneb, and rotenone causes lipid peroxidation and protein misfolding that affects cell death through members of the Bcl-2 family. Sufficient activation of Bax and Bak facilitates mitochondrial outer-membrane permeabilization, which releases death-inducing factors that cause apoptotic and nonapoptotic programmed cell death. The formation of alpha-synuclein aggregates is a defining pathologic feature of PD and is induced by these neurotoxins as well as several Parkinson-linked familial mutations. Of the familial mutations identified thus far, two of the loci encode proteins associated with ubiquitin-proteasome degradation of misfolded proteins (Parkin and Uch-L1), and two encode proteins associated with mitochondria and oxidative stress (DJ-1 and PINK1). Both gene and toxin findings indicate that dopaminergic neuron losses in PD are the result of oxidative stress affecting mitochondria function and ubiquitin-proteasome activity. Here we describe how related cell death mechanisms are involved in the pathophysiology of Parkinson's disease.
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PMID:Parkinson-linked genes and toxins that affect neuronal cell death through the Bcl-2 family. 1871 46

LRRK2, alpha-synuclein, UCH-L1 and DJ-1 are implicated in the etiology of Parkinson's disease. We show for the first time that increase in striatal alpha-synuclein levels induce increased Lrrk2 mRNA levels while Dj-1 and Uch-L1 are unchanged. We also demonstrate that a mouse strain lacking the dopamine signaling molecule DARPP-32 has significantly reduced levels of both Lrrk2 and alpha-synuclein, while mice carrying a disabling mutation of the DARPP-32 phosphorylation site T34A or lack alpha-synuclein do not show any changes. To test if striatal dopamine depletion influences Lrrk2 or alpha-synuclein expression, we used the neurotoxin 6-hydroxydopamine in rats and MitoPark mice in which there is progressive degeneration of dopamine neurons. Because striatal Lrrk2 and alpha-synuclein levels were not changed by dopamine depletion, we conclude that Lrrk2 and alpha-synuclein mRNA levels are possibly co-regulated, but they are not influenced by striatal dopamine levels.
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PMID:Lrrk2 and alpha-synuclein are co-regulated in rodent striatum. 1879 59

Parkinson disease (PD) is characterized by the presence of ubiquitylated inclusions and the death of dopaminergic neurons. Seven in absentia homolog (SIAH) is a ubiquitin-ligase that ubiquitylates alpha-synuclein and synphilin-1 and is present in Lewy bodies of PD patients. Understanding the mechanisms that regulate the ubiquitylation of PD-related proteins might shed light on the events involved in the formation of Lewy bodies and death of neurons. We show in this study that the recently described synphilin-1 isoform, synphilin-1A, interacts in vitro and in vivo with the ubiquitin-protein isopeptide ligase SIAH and regulates its activity toward alpha-synuclein and synphilin-1. SIAH promotes limited ubiquitylation of synphilin-1A that does not lead to its degradation by the proteasome. SIAH also increases the formation of synphilin-1A inclusions in the presence of proteasome inhibitors, supporting the participation of ubiquitylated synphilin-1A in the formation of Lewy body-like inclusions. Synphilin-1A/SIAH inclusions recruit PD-related proteins, such as alpha-synuclein, synphilin-1, Parkin, PINK1, and UCH-L1. We found that synphilin-1A robustly increases the steady-state levels of SIAH by decreasing its auto-ubiquitylation and degradation. In addition, synphilin-1A blocks the ubiquitylation and degradation of the SIAH substrates synphilin-1 and deleted in colon cancer protein. Furthermore, synphilin-1A strongly decreases the monoubiquitylation of alpha-synuclein by SIAH and the formation of alpha-synuclein inclusions, supporting a role for monoubiquitylation in alpha-synuclein inclusion formation. Our results suggest a novel function for synphilin-1A as a regulator of SIAH activity and formation of Lewy body-like inclusions.
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PMID:Synphilin-1A inhibits seven in absentia homolog (SIAH) and modulates alpha-synuclein monoubiquitylation and inclusion formation. 1922 63

The inverse association of the functional ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y variant with Parkinson's disease (PD) among Caucasian populations has been debated. We conducted a large-scale analysis to investigate the age-of-onset effect of the UCHL1 variant in PD among ethnic Chinese. Individual data sets from 5 centers comprising a total of 4088 study subjects were analyzed. In the univariate analysis, only data from 1 center showed a trend towards a protective effect among young subjects. However, in the combined analysis, no significant association between the UCHL1 variant and PD was detected (A allele frequency 0.531 vs. 0.528, p=0.87, OR 1.01, 95% CI 0.92-1.1). Among subjects less than 60 years old, the OR is 0.99 (95% CI 0.84-1.16, p=0.88). A multivariate logistic regression analysis showed that family history, UCHL1 variant and the interaction of UCHL1 variant and age at onset (p=0.816) were not significantly associated with PD.
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PMID:Analysis of the UCHL1 genetic variant in Parkinson's disease among Chinese. 1932 25

Dopamine oxidation has been previously demonstrated to cause dysfunction in mitochondrial respiration and membrane permeability, possibly related to covalent modification of critical proteins by the reactive dopamine quinone. However, specific mitochondrial protein targets have not been identified. In this study, we utilized proteomic techniques to identify proteins directly conjugated with (14)C-dopamine from isolated rat brain mitochondria exposed to radiolabeled dopamine quinone (150 microM) and differentiated SH-SY5Y cells treated with (14)C-dopamine (150 microM). We observed a subset of rat brain mitochondrial proteins that were covalently modified by (14)C-dopamine, including chaperonin, ubiquinol-cytochrome c reductase core protein 1, glucose regulated protein 75/mitochondrial HSP70/mortalin, mitofilin, and mitochondrial creatine kinase. We also found the Parkinson's disease associated proteins ubiquitin carboxy-terminal hydrolase L1 and DJ-1 to be covalently modified by dopamine in both brain mitochondrial preparations and SH-SY5Y cells. The susceptibility of the identified proteins to covalent modification by dopamine may carry implications for their role in the vulnerability of dopaminergic neurons in Parkinson's disease pathogenesis.
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PMID:Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. 1933 21

UCH-L1 is a member of the family of ubiquitin C-terminal hydrolases whose primary role is to hydrolyze small C-terminal adducts of ubiquitin to generate free ubiquitin monomers. Expression of UCH-L1 is highly specific to neurons and point mutations in this enzyme are associated with a hereditary form of Parkinson's disease. Herein, we present the NMR backbone assignments of human UCH-L1, thus enabling future solution-state NMR spectroscopic studies on the structure and function of this important protein.
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PMID:Backbone assignments of the 26 kDa neuron-specific ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). 2001 16


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