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)

Mutations in two genes, alpha-synuclein and parkin, have been identified as some rare causes for familial Parkinson's disease (PD). alpha-Synuclein and parkin protein have subsequently been identified in Lewy bodies (LB). To gain further insight into the pathogenesis of PD we investigated the role of neurofilament light (NF-L), another component of LB aggregation. A detailed mutation search of the NF-L gene in 328 sporadic and familial PD patients of German ancestry revealed three silent DNA changes (G163A, C224T, C487T) in three unrelated patients. Analysis of the promoter region of the NF-L gene identified a total of three base pair substitutions defining five haplotypes. Association studies based on these haplotypes revealed no significant differences between PD patients and 344 control individuals. Therefore, NF-L is unlikely to play a major role in the pathogenesis of PD.
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PMID:Neurofilament L gene is not a genetic factor of sporadic and familial Parkinson's disease. 1223 60

Many studies have suggested the ubiquitin-proteasome system played an essential role in the pathogenesis of neurodegenerative disorders. In 1999, we provided evidence that a mutation of the system could directly cause neurodegeneration using the gad mouse. Namely, we identified the gad mutation was caused by an intragenic deletion of a gene encoding ubiquitin C-terminal hydrolase 1(UCH-L1), which is a member of de-ubiquitinating enzyme family. In human, missense mutation of UCH-L1 gene was reported in a German family with Parkinson's disease. As well, the parkin gene product was revealed to be an E3 ubiquitin ligase which recognize a form of alpha-synuclein as a substrate. Thus, the investigation of the ubiquitin-proteasome system should provide a clue for understanding neurodegeneration. We have characterized UCH-L1 and identified candidates of endogenous substrates as well as interacting proteins of UCH-L1. In addition, we found amount of monomeric ubiquitin was decreased in the brain of the gad mouse compared with wild type mice. We have also tried to develop "protein therapy" using UCH-L1 protein with TAT sequence. We observed the protein was delivered to brain after intraperitoneal injection in the wild type mouse. This approach would provide a new therapeutic strategy for neurodegeneration.
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PMID:[The ubiquitin-proteasome system and neurodegeneration]. 1223 99

Molecular and clinical characterization of parkin-associated parkinsonism is well described; however, there are no data available on progression of dopamine terminal dysfunction in parkin-associated disease. We have used [(18)F]dopa PET serially to study members of a family with young-onset parkinsonism who are compound heterozygous for mutations in the parkin gene, having an exonic deletion and a novel intronic splice site mutation. Four patients have been studied twice, 10 years apart, to assess disease progression. Additionally, we have studied five asymptomatic family members, four of whom carry a single parkin mutation and one individual who has a normal genotype. Two of the carriers and the individual with the normal genotype had repeat [(18)F]dopa PET. The group of parkin patients showed a significantly slower loss of putamen [(18)F]dopa uptake (P = 0.0008) compared with a group of idiopathic Parkinson's disease (IPD) patients who had baseline putamen [(18)F]dopa uptake and disease severity similar to the parkin group. These results indicate that disease progression in patients with parkin mutations is slower than that of IPD patients. The group of asymptomatic parkin carriers also showed significant striatal dopaminergic dysfunction, and three of them developed subtle extrapyramidal signs. However, the two carriers scanned twice showed no progression over a 7-year period. The slower rate of disease progression in parkin patients may explain the near normal longevity of these patients with young onset parkinsonism.
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PMID:Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. 1224 82

Loss-of-function mutations in the parkin gene were first identified in autosomal recessive juvenile parkinsonism (AR-JP). Subsequently, parkin mutations were found in many early-onset patients with Parkinson's disease (PD) (<45 years at onset). We hypothesized that parkin gene expression also may contribute to the age-associated risk of idiopathic PD (>50 years at onset). Two single-nucleotide polymorphisms within the parkin core promoter have been identified and assessed. We show one of the variants, -258 T/G, is located in a region of DNA that binds nuclear protein from human substantia nigra in vitro and functionally affects gene transcription. Furthermore, the -258 T/G polymorphism is genetically associated with idiopathic PD, as assessed in a large population-based series of cases and controls. Our results further implicate the parkin gene in the development of Parkinson's disease.
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PMID:Functional association of the parkin gene promoter with idiopathic Parkinson's disease. 1237 68

Linkage of the Huntington's disease gene to chromosome 4 in 1983 marked the birth of modern genetics in movement disorders. The discovery that an expanded trinucleotide DNA repeat was central to the mechanism of this disease has been repeated over and over in a growing list of inherited ataxias. In 1997, a different mutation and genetic mechanism was discovered in a severe type of generalized primary torsion dystonia - Oppenheim's dystonia. Before this, only the genetic cause for rare metabolic dystonias was known, notably dopa-responsive (Segawa's) dystonia. In the same year, from the identification of mutation in the alpha-synuclein gene in rare pedigrees with autosomal dominant parkinsonism, arose the concept that Parkinson's disease may be part of a broader group of 'synucleinopathies', in which there is a fundamental defect in protein processing. In the following year, mutations in autosomal recessive juvenile onset parkinsonism were found in a gene called 'parkin'. Parkin mutations are a more common cause of parkinsonism than the rare alpha-synuclein mutations, particularly in young-onset disease. However, a most important understanding, occurring in the last year, has been the relationship between the parkin gene product, alpha-synuclein and abnormal protein degradation in the cell. A unified theory of neuronal death in Parkinson's disease is emerging, pointing to potential new therapies in the future.
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PMID:Genetics of movement disorders: an abbreviated overview. 1237 57

Cells in the brain deploy multiple mechanisms to maintain the integrity of nerve cell circuits, and to facilitate responses to environmental demands and promote recovery of function after injury. The mechanisms include production of neurotrophic factors and cytokines, expression of various cell survival-promoting proteins (e.g. protein chaperones, antioxidant enzymes, Bcl-2 and inhibitor of apoptosis proteins), protection of the genome by telomerase and DNA repair proteins, and mobilization of neural stem cells to replace damaged neurons and glia. The aging process challenges such neuroprotective and neurorestorative mechanisms, often with devastating consequences as in Alzheimer's disease (AD), Parkinson's and Huntington's diseases and stroke. Genetic and environmental factors superimposed upon the aging process can determine whether brain aging is successful or unsuccessful. Mutations in genes that cause inherited forms of AD (amyloid precursor protein (APP) and presenilins), Parkinson's disease (alpha-synuclein and parkin) and trinucleotide repeat disorders (e.g. huntingtin and the androgen receptor) overwhelm endogenous neuroprotective mechanisms. On the other hand, neuroprotective mechanisms can be bolstered by dietary (caloric restriction, and folate and antioxidant supplementation) and behavioral (cognitive and physical activities) modifications. At the cellular and molecular levels, successful brain aging can be facilitated by activating a hormesis response to which neurons respond by upregulating the expression of neurotrophic factors and stress proteins. Neural stem cells that reside in the adult brain are also responsive to environmental demands, and appear capable of replacing lost or dysfunctional neurons and glial cells, perhaps even in the aging brain. The recent application of modem methods of molecular and cellular biology to the problem of brain aging is revealing a remarkable capacity within brain cells for adaptation to aging and resistance to disease.
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PMID:Neuroprotective and neurorestorative signal transduction mechanisms in brain aging: modification by genes, diet and behavior. 1239 75

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as alpha-synuclein and parkin, suggest a role for the ubiquitin-proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause alpha-synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.
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PMID:Mechanistic approaches to Parkinson's disease pathogenesis. 1240 37

N-Methylated beta-carbolines, including 2-methylnorharman, are structural and functional analogs of the parkinsonian-inducing toxin, MPP+. We are investigating N-methylated beta-carbolines, including 2-methylnorharman, as possible etiologic factors in the pathogenesis of Parkinson's disease. The cellular targets of N-methylated beta-carboline-mediated cytotoxicity are unknown; therefore, we used the T7Select Phage Display System in a novel approach to identify brain proteins that bind to 2-methylnorharman. We incubated (biopanned) immobilized 2-methylnorharman with a phage display cDNA library that expressed a library of human brain proteins on the surface of bacteriophage T7. We washed off unbound phage, amplified the phage that were bound to 2-methylnorharman, and enriched for toxin-interacting phage by repeating the biopanning and amplification steps. The cDNA sequences from the toxin-interacting phage were used to derive the amino acid sequences of the phage-displayed proteins. Five of the six 2-methylnorharman-interacting proteins may have relevance to Parkinson's disease: alpha-tubulin, paraoxonase, dorfin, fatty acid binding protein, and platelet-activating factor acetylhydrolase. Dorfin has sequence homology with parkin, which is interesting because mutations in the parkin gene associate with early-onset Parkinson's disease. Our findings are the basis for future studies aimed at determining whether 2-methylnorharman affects the function of these specific proteins in vitro and in vivo.
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PMID:Identification of brain proteins that interact with 2-methylnorharman. An analog of the parkinsonian-inducing toxin, MPP+. 1241 54

Ubiquitylated protein aggregates are characteristic features of neurodegenerative disorders that are also found in acute pathological states of the brain such as stroke. Many of the proteins connected to neurodegenerative diseases play a role in the ubiquitin-proteasomal pathway. Mutation of one of these proteins, the E3 ubiquitin ligase parkin, is the cause of autosomal recessive juvenile Parkinson's disease. Here we show that transient focal cerebral ischemia of 1-h duration induces marked depletion of parkin protein levels, to 60%, 36%, 33%, and 25% of controls after 1, 3, 6, and 24 h of reperfusion, but that ischemia does not cause lower protein levels of E2 ubiquitin-conjugating enzymes Ubc6, Ubc7, or Ubc9. After 3 h of reperfusion, when parkin protein levels were already reduced to <40% of control, ATP levels were almost completely recovered from ischemia and we did not observe DNA fragmentation, suggesting that parkin depletion preceded development of neuronal cell death. Up-regulation of the expression of parkin has been shown to protect cells from injury induced by endoplasmic reticulum (ER) dysfunction, and this form of cellular stress is also triggered by transient cerebral ischemia. However, in contrast to observations in neuroblastoma cells, we saw no up-regulation of parkin expression in primary neuronal cell cultures after induction of ER dysfunction. Our data thus suggest that ischemia-induced depletion of parkin protein may contribute to the pathological process resulting in cell injury by increasing the sensitivity of neurons to ER dysfunction and the aggregation of ubiquitylated proteins during the reperfusion period.
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PMID:Down-regulation of parkin protein in transient focal cerebral ischemia: A link between stroke and degenerative disease? 1241 19

Genes of the RBR family are characterized by the RBR signature (two RING finger domains separated by an IBR/DRIL domain). The RBR family is widespread in eukaryotes, with numerous members in animals (mammals, Drosophila, Caenorhabditis) and plants (Arabidopsis). But yeasts, such as Saccharomyces cerevisiae or Schizosaccharomyces pombe, contain only two RBR genes. We determined the phylogenetic relationships and the most likely orthologs in different species of several family members for which functional data are available. These include: (1) parkin, whose mutations are involved in forms of familial Parkinson's disease; (2) the ariadne genes, recently characterized in Drosophila and mammals; (3) XYbp and Dorfin, two mammalian genes whose products interact with the centrosome; (4) XAP3, RBCK1, and UIP28, mammalian genes encoding Protein Kinase-C-binding proteins; and (5) ARA54, an androgen receptor coactivator. Because several of these genes are involved in ubiquitination, we used phylogenetic and structural analyses to explore the hypothesis that all RBR proteins might play a role in ubiquitination. We show that the involvement of RBR proteins in ubiquitination predates the animals-plants-fungi divergence. On the basis of the evidence provided by cases of gene fusion, we suggest that Ariadne proteins interact with cullin domain-containing proteins to form complexes with ubiquitin-ligase activity.
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PMID:Comparative genomics of the RBR family, including the Parkinson's disease-related gene parkin and the genes of the ariadne subfamily. 1244 96


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