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)

Several neurological diseases which affect the corpus striatum are candidates for gene therapy. We have developed a defective Herpes Simplex Virus (HSV-1) vector system to introduce genes into postmitotic cells, such as neurons. The prototype vector, pHSVlac, contains a transcription unit which places the E. coli Lac Z gene under the control of the HSV-1 immediate early (IE) 4/5 promoter, a constitutive promoter. We now demonstrate that a HSV-1 vector can deliver a gene into striatal neurons. Infection of cultured rat striatal neurons with pHSVlac virus resulted in stable expression of beta-galactosidase for at least two weeks, without cell death. The potential to replace the Lac Z gene with other genes of interest, such as the gene responsible for Huntington's Disease, once it is isolated, may lead to insights about the pathogenesis of this genetic neurodegenerative disease, and may provide a method for performing gene therapy on this disease. Similarly, introduction of the tyrosine hydroxylase gene, which encodes the rate-limiting enzyme in the conversion of tyrosine to dopamine, into striatal neurons might provide a novel gene therapy approach towards treating Parkinson's Disease.
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PMID:Infection of cultured striatal neurons with a defective HSV-1 vector: implications for gene therapy. 166 13

To package classical neurotransmitters into vesicles so that their release can be regulated by activity, neuronal cells express a set of specific vesicular transport proteins. We have used selection in MPP+ to clone the cDNAs encoding two vesicular monoamine transporters, the first members of this novel gene family that now also includes the vesicular transporter for acetylcholine. The sequences show similarity to several bacterial antibiotic resistance proteins, further supporting a role in detoxification and possibly Parkinson's disease. The two vesicular amine transporters show differences in their affinity for substrates, their turnover number and their pharmacology. In particular, the proteins differ in their interactions with the potent inhibitor tetrabenazine and with amphetamines, accounting for several classic pharmacological observations. Since the subcellular localization of the transport proteins determines the site of monoamine storage and the site of monoamine storage appears to differ from other classical transmitters, we have also raised polyclonal antibodies to the transporters and used these to demonstrate localization in dense core vesicles rather than synaptic vesicles. In addition to the implications for monoamine release, these observations also indicate a vesicular amine transporter as the first integral membrane protein restricted to the regulated secretory pathway.
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PMID:A molecular analysis of vesicular amine transport. 878 77

The autosomal recessive mutation mnd2 is responsible for a lethal neuromuscular wasting disorder in the mouse. A high-resolution genetic map of the mnd2 region of mouse chromosome 6 was generated by analysis of 1147 F2 offspring from an intersubspecific cross between strains C57BL/6J-mnd2/+ and CAST/Ei. The results localize mnd2 to the 0.2-cM interval between D6Mit164 and D6Mit128. A contig of overlapping YAC, BAC, and P1 clones spanning the nonrecombinant interval was constructed. One novel gene isolated from the contig, D6Mm3e, is a new member of the WD repeat gene family. The observed gene order for the five positional candidate genes previously mapped to the region and five newly isolated genes is centromere-Hexokinase II-D6Mm5e-p62 Dok-Aup1-Rhotekin, D6Mm3e-Dynactin 1-Smooth muscle gamma actin-D6Mm4e-beta-adducin-telomere. Seven of these genes are located within the 400-kb nonrecombinant interval for mnd2. Comparison between wildtype and mutant failed to detect any differences in mRNA size, abundance, or coding sequence for these seven genes. The genes described here are positional candidates for the Parkinson disease susceptibility locus PARK3 that was recently mapped to the corresponding region of human chromosome band 2p13.1.
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PMID:High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6. 980 35

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.
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PMID:Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease. 985 85

Autosomal recessive juvenile parkinsonism (AR-JP) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with onset before age 40 years and a slowly progressive course. Families with this condition have been described predominantly in Japanese population, occasionally under different names including an autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF) or a familial form of juvenile parkinsonism. Recently, the causative gene for AR-JP was mapped on chromosome 6q25.2-q27, and subsequently a novel gene 'parkin' was identified by means of positional cloning. In this manuscript, we review the clinical, pathological and genetical aspects of AR-JP. It would not only promise to provide important insights into the molecular mechanisms of selective degeneration of dopaminergic neurons in AR-JP, but also bring insights into the mechanisms of degeneration of these neurons in Parkinson's disease.
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PMID:Autosomal recessive juvenile parkinsonism. 1098 71

Parkinson's disease is a common neurodegenerative disease with complex clinical features. Recently, we idenfied a novel gene named Parkin to be responsible for the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP). Various mutations were found in AR-JP patients of Japanese and other ethnic origins, providing a definitive evidence for the Parkin to be a causative gene for AR-JP. The predicted structure of Parkin protein and its mutation provide important clues for studying the functional role of the Parkin protein in leading to selective degeneration of nigral neurons in the brains of AR-JP patients.
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PMID:PARKIN as a pathogenic gene for autosomal recessive juvenile parkinsonism. 1112 8

Parkin is the causative gene for an autosomal recessive form of Parkinson's disease. The gene was discovered in 1998. The parkin gene is a novel gene containing 12 exons spanning over 1.5 Mb and encodes a protein of 465 amino acids with a molecular mass of approximately 52,000 M(r). Various deletion mutations and point mutations have been discovered in patients with autosomal recessive Parkinson's disease. The substantia nigra and the locus coeruleus selectively undergo neurodegeneration without forming Lewy bodies. The parkin gene product, Parkin protein, has a unique structure with a ubiquitin-like domain in the amino-terminus and a RING finger motif in the carboxy terminus. The function of Parkin was not known until recently. During the year 2000, great progress was made in defining its function. First of all, Parkin was found to be a ubiquitin-protein ligase (E3), a component of the ubiquitin system, which is an important adenosine triphosphate-dependent protein degradation machinery. In addition, CDCrel-1, a synaptic vesicle associated protein, was found to be a substrate for Parkin as an E3. Although many studies still need to be performed to elucidate the molecular mechanism of the selective nigral neurodegeneration in this form of familial Parkinson's disease, it will not be too long before this is accomplished. In this review article, we evaluate the developments in this area published since 1 February 2000.
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PMID:Parkin and Parkinson's disease. 1147 Sep 64

A novel gene for Parkinson's disease (PD), DJ-1, has been identified that encodes a multifunctional product with several known protein-protein interactions and effects on gene expression. Here, I outline how it is possible to construct hypotheses that place DJ-1 in different relationships to the other known PD genes, alpha-synuclein and parkin. The identification of multiple genetic causes will provide further impetus to describe the pathway leading to PD.
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PMID:Pathways to Parkinsonism. 1252 67

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. It is urgently needed to elucidate the cause of the disease and to establish neuroprotective treatment. We have been working on the etiology and pathogenesis of PD for many years and we found selective loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the nigral neurons of patients with PD. Our observation firmly established mitochondrial defects in PD. Mitochondrial respiratory failure induces oxidative damage in neurons, and we found increase in hydroxynonenal and 8-oxo-deoxyguanine, indices of oxidative damage, in the nigral neurons of PD. These abnormalities can trigger apoptotic cell death. The primary events which induce mitochondrial failure and oxidative damage are not known, however, it has been postulated that the interaction of genetic risk factors and environmental factors would initiate the degenerative process. Based on this assumption, we conducted genetic association studies by the candidate gene methods. We found that polymorphic mutations of superoxide dismutase-2 and 24-kDa subunit of mitochondrial complex I were associated increased risk of developing Parkinson's disease. While we were doing this genetic association study, we found a family, in which parkinsonian phenotype completely segregated with a polymorphic mutation of the superoxide dismutase-2 gene. In this family, 4 out of 6 siblings were affected with early onset parkinsonism and the parents were apparently normal. Thus the mode of inheritance appeared to be autosomal recessive and this type is now called as AR-JP or Park2. We confirmed the linkage of this type of familial Parkinson's disease to the superoxide dismutase loci that is located in the telomeric region of chromosome 6 by the linkage analysis using microsatellite markers in this region. Then we found another family, in which an affected patient showed lack of one of the microsatellite markers (D6S315), which we were using in the linkage analysis. This observation prompted us to initiate the molecular cloning of the disease gene utilizing D6S315 as the initial probe. The molecular cloning was done with the collaboration with Professor Nobuyoshi Shimizu of Keio University. We identified a novel gene and confirmed that mutations of this novel gene were found only in the patients with autosomal recessive Parkinson's disease. The novel gene was named parkin. We conducted mutational analysis on more than 700 families with Parkinson's disease. We also established a method to detect compound heterozygotes of parkin mutations. Mutinous of the parkin gene were found in approximately 50% of autosomal recessive families. Many kinds of exonic deletions and point mutations were found. This type of familial Parkinson's disease had been considered to be unique among Japanese, but since we started mutational analysis of the parkin gene, we confirmed the world wide distribution of parkin gene mutations. Then we analyzed functions of parkin protein with the collaboration with Dr. Keiji Tanaka of Tokyo Metropolitan Institute of Medical Sciences. We found that parkin protein was a ubiquitin-protein ligase of the ubiquitin system. Now we are working on the candidate substrates of parkin protein as a ubiquitin ligase. We found that CDCrel-1, a synaptic vesicle protein, was a candidate substrate of parkin protein. In addition, we found two additional candidate proteins, i.e., alpha-synuclein 22 and PAEL receptor, with the collaboration of Professor Denis Selkoe of Harvard Medical School and Dr. Ryosuke Takahashi of RIKEN, respectively. Accumulation of PAEL receptor in the endoplasmic reticulum causes endoplasmic reticulum stress and apoptotic cell death. We found evidence to indicate accumulation of PAEL receptor and the presence of endoplasmic reticulum stress in a patient with AR-JP (Park2). Thus our studies firmly established that a genetic defect of an enzyme in the ubiquitin-proteasome system induces selective nigral neuronal death. We indicated the important role of the ubiquitin-proteasome system in neurodegeneration in general. In many other neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, Machado-Joseph disease, dentatorubral-pallidoluysian atrophy, and ALS, ubiquitinated proteins are accumulated in neurons. Thus protein handling in the ubiquitin-proteasome system appears to be affected in these neurodegenerative disorders despite the difference in the primary defects. Our studies also suggest many potential approaches for the discovery of neuroprotective treatment for not only Parkinson's disease but also other neurodegenerative disorders.
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PMID:[Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease]. 1528 6

Mutations in the PINK1 gene (PARK6), a putative serine-threonine kinase, cause autosomal recessive Parkinson's disease. PINK1 functions as a protein kinase and confers protective effects in the mitochondria, where it is primarily located. We assessed in a population of European ancestry whether common genetic variation in this novel gene influences nonmendelian forms of Parkinson's disease. We defined the linkage disequilibrium structure of PINK1 and used this to identify a set of tagging single nucleotide polymorphisms that we estimate will efficiently represent all of the common DNA variation in the entire gene. Genotyping these tags in a set of 576 Parkinson's disease patients and 514 controls did not demonstrate a case-control partition for allele or for haplotype and thus provides evidence against the existence of a common functional variants in PINK1 that has a strong influence on PD risk.
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PMID:The gene responsible for PARK6 Parkinson's disease, PINK1, does not influence common forms of parkinsonism. 1534 59


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