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's Disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCHL1). All three PD-linked gene products are related directly or indirectly to the functioning of the cellular ubiquitin proteasomal system (UPS), suggesting that UPS dysfunction may be important in PD pathogenesis. Indeed, emerging evidence indicates that derangements of the UPS may be one of the underlying mechanisms of PD pathogenesis. The function of parkin as an ubiquitin protein ligase positions it as an important player in both familial and idiopathic PD. We recently demonstrated that parkin mediates a nondegradative form of ubiquitination on synphilin-1 that could contribute to synphilin-1's aggregation in PD. Our results implicate parkin involvement in the formation of Lewy bodies associated with sporadic PD. This review discusses the role of the UPS, as well as the modus operandi of the three PD candidate felons (alpha-synuclein, parkin, and UCHL1) along with their conspirators in bringing about dopaminergic cell death in PD.
 ...
PMID:The cast of molecular characters in Parkinson's disease: felons, conspirators, and suspects. 1284 76

Neuronal ubiquitin C-terminal hydrolase (UCH-L1) has been linked to Parkinson's disease (PD), the progression of certain nonneuronal tumors, and neuropathic pain. Certain lung tumor-derived cell lines express UCH-L1 but it is not expressed in normal lung tissue, suggesting that this enzyme plays a role in tumor progression, either as a trigger or as a response. Small-molecule inhibitors of UCH-L1 would be helpful in distinguishing between these scenarios. By utilizing high-throughput screening (HTS) to find inhibitors and traditional medicinal chemistry to optimize their affinity and specificity, we have identified a class of isatin O-acyl oximes that selectively inhibit UCH-L1 as compared to its systemic isoform, UCH-L3. Three representatives of this class (30, 50, 51) have IC(50) values of 0.80-0.94 micro M for UCH-L1 and 17-25 micro M for UCH-L3. The K(i) of 30 toward UCH-L1 is 0.40 micro M and inhibition is reversible, competitive, and active site directed. Two isatin oxime inhibitors increased proliferation of the H1299 lung tumor cell line but had no effect on a lung tumor line that does not express UCH-L1. Inhibition of UCH-L1 expression in the H1299 cell line using RNAi had a similar proproliferative effect, suggesting that the UCH-L1 enzymatic activity is antiproliferative and that UCH-L1 expression may be a response to tumor growth. The molecular mechanism of this response remains to be determined.
 ...
PMID:Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. 1452 54

Three genes, alpha-synuclein, parkin, and ubiquitin C-terminal hydrolase L1 (UCH-L1), have been associated with inherited forms of Parkinson's disease (PD), although their in vivo functions have remained largely unknown. To develop an animal model for the molecular study of PD, we cloned zebrafish uch-L1 cDNA and its gene promoter. Sequence analysis revealed that the zebrafish Uch-L1 is highly homologous (79%) to the human UCH-L1, which is a member of the deubiquitinating enzymes. By whole-mount in situ hybridization, we examined the spatiotemporal expression of uch-L1 mRNA in developing zebrafish embryos. The uch-L1 mRNAs are detected in neuronal cells at the first day of embryo development. The expression domain of uch-L1 overlaps with that of tyrosine hydroxylase, a molecular marker for dopaminergic neurons, in the ventral diencephalon, an equivalent structure to the substantia nigra where PD progresses in human. To further analyze the tissue-specific regulation of uch-L1 gene expression, we also tested its gene promoter activity and showed a preferential neuronal expression in transient transgenic zebrafish embryos. These results suggest that uch-L1 may have an important role in the development of neuronal cells in early embryos as well as in the degeneration and disease of neuronal cells in late adult brain.
 ...
PMID:Cloning and expression analysis of a Parkinson's disease gene, uch-L1, and its promoter in zebrafish. 1468 Aug 7

Genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted based on the studies of the familial form of the disease and progress in molecular genetic techniques. To date, specific mutations have been identified in five separate genes and several chromosomal loci have been linked for different forms of familial parkinsonism. The discovery of alpha-synuclein, ubiquitin C-terminal hydrolase, parkin, tau and DJ-1 mutations and analysis of the biochemical and molecular properties of these gene products point to the critical role of protein aggregation in dopaminergic neurons of the substantia nigra as the basic mechanism leading to neurodegeneration also in sporadic form of the disease. Lewy bodies, even in sporadic PD, contain some of these gene products, particularly abundant fibrillar alpha-synuclein. Studies of familial parkinsonism provide evidence that PD is genetically heterogeneous. Evidence elucidated from genetic studies in PD suggests that parkinsonism is a complex disorder in which multiple gene-gene and gene-environment interactions play a critical role in the development of the disease and phenotypic variability. Further genetic studies in familial parkinsonism will enhance our knowledge of pathogenesis of PD and allow the development of neuroprotective treatments of PD and perhaps other forms of parkinsonism as well.
 ...
PMID:[Advances in the genetic studies in Parkinson's disease]. 1530 6

Parkinson's disease (PD) is a multifactorial disease that appears to arise from the effects of both genetic and environmental influences. Pesticides and heavy metals are the principle environmental factors that appear to impact on PD. The known genetic factors include multiple genes that have been identified in related parkinsonian syndromes, as well as alpha-synuclein. Genes associated with either PD or Parkinson-related disorders include parkin, DJ-1, ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1), nuclear receptor-related factor 1, and alpha-synuclein. Alpha-synuclein is particularly notable because it aggregates readily and is the main component of Lewy bodies (LBs). Aggregated alpha-synuclein binds the proteasome and potently inhibits proteasomal activity. Because ubiquitin accumulates in LBs, and parkin and UCH-L1 also interact with the ubiquitin proteasomal system, proteasomal dysfunction is thought to contribute to the pathophysiology of PD. Increasing numbers of experiments suggest that neurotoxins might interact with alpha-synuclein or other Parkinson-related proteins to contribute to the pathophysiology of PD. Transgenic animal models overexpressing alpha-synuclein develop age-dependent motor dysfunction and inclusions in the brain stem that contain alpha-synuclein. These models are very helpful in elucidating the pathophysiology of PD but do not completely recapitulate the disease process. The relationship between these transgenic models and PD is a subject of intense investigation.
 ...
PMID:Pathological proteins in Parkinson's disease: focus on the proteasome. 1565 64

PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including alpha-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable alpha-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
 ...
PMID:Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. 1604 50

The ubiquitin C-terminal hydrolase UCH-L1 (PGP9.5) comprises >1% of total brain protein but is almost absent from other tissues [Wilkinson, K. D., et al. (1989) Science 246, 670-673]. Mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from Parkinson's disease [Leroy, E., et al. (1998) Nature 395, 451-452; Maraganore, D. M., et al. (1999) Neurology 53, 1858-1860]. Abnormal overexpression of UCH-L1 has been shown to correlate with several forms of cancer [Hibi, K., et al. (1998) Cancer Res. 58, 5690-5694]. Because the amino acid sequence of UCH-L1 is similar to that of other ubiquitin C-terminal hydrolases, including the ubiquitously expressed UCH-L3, which appear to be unconnected to neurodegenerative disease, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable importance. We have determined the three-dimensional structure of human UCH-L1 at 2.4-A resolution by x-ray crystallography. The overall fold resembles that of other ubiquitin hydrolases, including UCH-L3, but there are a number of significant differences. In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements.
 ...
PMID:Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. 1653 82

Since the first description of Parkinson's disease (PD) in 1817 attempts have been made to resolve the etiology of this common neurodegenerative disorder. In the last century the influence of heredity in PD was controversial. The identification of mutations in six genes responsible for Mendelian forms of PD; alpha-synuclein (SNCA), parkin (PRKN), ubiquitin C-terminal hydrolase L1 (UCH-L1), oncogene DJ-1, PTEN-induced putative kinase 1 (PINK1), and most recently leucine-rich repeat kinase 2 (LRRK2), has confirmed the role of genetics in familial forms of the disease. The exact relationship of these familial disorders and related genes to the more common sporadic form is currently uncertain. The identification of LRRK2 mutations and the association of common variants in SNCA and UCH-L1 in apparently sporadic late-onset disease indicate these genes may be of greater importance than previously believed. The protein products of the six genes are involved in different pathways of neurodegeneration and have opened new avenues of research. This focused research will lead to the development of novel targeted therapies, which may revolutionize the treatment of PD for a substantial proportion of patients.
 ...
PMID:Parkinson's disease: the genetics of a heterogeneous disorder. 1679 86

Excessive accumulation of alpha synuclein (a-syn) in the brain has been implicated in several degenerative neurological disorders, most notably Parkinson's disease. The aggregation of a-syn is the major component of intraneuronal inclusions, Lewy bodies, which are neuropathological features, observed in Parkinson's disease, Lewy body dementia, and other synucleopathies. Diverse cellular events can contribute to a-syn accumulation, aggregation, and to subsequent Lewy body formation. These factors include genetic mutations of synuclein, parkin, or the deubiquitinating enzyme, ubiquitin C-terminal hydrolase (UCH-L1), leading to reduced clearance of a-syn by the ubiquitin proteasomal pathway (UPP). Furthermore, intracellular insults include environmental factors and an age-related decrement in antioxidant defense systems that increase oxidative stress and can affect either the accumulation or clearance of a-syn. We have dynamically modeled a-syn processing in normal and in several disease states; focusing upon alterations in the aggregation and clearance of a-syn as influenced by the UPP and the oxidative stress pathways. Simulation of increased oxidative stress generates a free radical profile analogous to that reported in vivo following exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Varying model parameters of oxidative stress, UPP dysfunction, or both pathways, simulate kinetics of a-syn that corresponds with the neuropathology described for the sporadic and genetic forms of Parkinson's disease. This in silico model provides a mathematical framework that enables kinetic appraisal of pathway components to better identify and validate important pharmacological targets.
 ...
PMID:Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease. 1692 Feb 72

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. The I93M mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with familial PD, and we have previously shown that the I93M UCH-L1-transgenic mice exhibit dopaminergic cell loss. Over 90% of neurodegenerative diseases, including PD, occur sporadically. However, the molecular mechanisms underlying sporadic PD as well as PD associated with I93M UCH-L1 are largely unknown. UCH-L1 is abundant (1-5% of total soluble protein) in the brain and is a major target of oxidative/carbonyl damage associated with sporadic PD. As well, abnormal microtubule dynamics and tubulin polymerization are associated with several neurodegenerative diseases including frontotemporal dementia and parkinsonism linked to chromosome 17. Here we show that familial PD-associated mutant UCH-L1 and carbonyl-modified UCH-L1 display shared aberrant properties: compared with wild-type UCH-L1, they exhibit increased insolubility and elevated interactions with multiple proteins, which are characteristics of several neurodegenerative diseases-linked mutants. Circular dichroism analyses suggest similar structural changes in both UCH-L1 variants. We further report that one of the proteins interacting with UCH-L1 is tubulin, and that aberrant interaction of mutant or carbonyl-modified UCH-L1 with tubulin modulates tubulin polymerization. These findings may underlie the toxic gain of function by mutant UCH-L1 in familial PD. Our results also suggest that the carbonyl modification of UCH-L1 and subsequent abnormal interactions of carbonyl-modified UCH-L1 with multiple proteins, including tubulin, constitute one of the causes of sporadic PD.
 ...
PMID:Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1. 1825 96


<< Previous 1 2 3 Next >>