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)

DJ-1 has recently been shown to be responsible for onset of familial Parkinson's disease (PD), PARK7. DJ-1 has been shown to play roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to trigger onset of PD. In this study, a recombinant DJ-1 protein was administrated into the brain of PD model rats that had been injected to 6-hydroxydopamine (6-OHDA) in the left substantia nigra. PD phenotypes, including dopaminergic neuron death in the substantia nigra, decrease in dopamine, and dopamine transporter levels in the striatum, and motor abnormality, were dramatically improved by wild-type DJ-1 but not L166P DJ-1, a mutant form of DJ-1 found in PD patients. Furthermore, production of reactive oxygen species and cell death induced by 6-OHDA in SH-SY5Y cells and mesencephalic neurons were inhibited by addition of the recombinant DJ-1. These findings suggest that DJ-1 is a therapeutic target for PD.
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PMID:PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson's disease rat model. 1686 May 63

Inherited mutations in PARK7, the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. Like human DJ-1 (hDJ-1), Drosophila DJ-1b protects against oxidative insult and is modified with oxidation. We demonstrate that hDJ-1 rescues flies mutant for DJ-1b, and that a conserved cysteine residue in the fly protein (C104, analogous to C106 in hDJ-1) is critical for biological antioxidant function in vivo. Targeted mutagenesis suggests that modification of DJ-1b at this residue inactivates the protective activity of the protein against oxidative stress. Further studies show that DJ-1 modification increases dramatically with age in flies, mice, and humans, with aged flies showing strikingly increased susceptibility to oxidative stress and markedly enhanced DJ-1b modification upon oxidative challenge. Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson's disease.
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PMID:Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. 1689 67

The identification of single genes linked to heritable forms of Parkinson disease (PD) has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. Detailed analyses of individuals with mutations in SNCA, Parkin, PINK1, DJ1 or LRRK2 have greatly advanced our knowledge of preclinical and clinical, morphological, and pathological changes in PD. These genetic breakthroughs have had profound implications for scientists, neurologists and patients alike. Such advances have provided unique opportunities to pursue the mechanisms of neuronal degeneration in models of PD pathogenesis, thereby reinforcing the significance of oxidative stress and mitochondrial dysfunction. With emerging clues from familial variants, researchers have begun to explore factors that lead to the expression of the more common, sporadic disease phenotype (idiopathic PD), including interactions between various genes, modifying effects of susceptibility alleles and epigenetic factors, and the influence of environmental agents and aging on the expression of PD-linked genes. These genetic leads have added to the urgency of developing translational drug treatments, and neurologists and their patients are confronting considerations relating to DNA testing. In this article, we summarize recent progress in establishing a neurogenetic component of PD, emphasize the need for developing PD biomarkers to improve diagnostic accuracy (in both clinical practice and therapeutic trials), and discuss scenarios in which specific DNA tests might be considered for diagnostic purposes. In the absence of consensus guidelines for DNA testing in PD and of any neuroprotective treatment for this nonfatal disorder, we remind ourselves of the omnipresent mandate, 'Primum nil nocere!' ('First, do no harm!').
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PMID:The genetics of Parkinson disease: Implications for neurological care. 1693 40

DJ-1 was initially identified by us as a novel oncogene and has recently been found to be a causative gene for familial Parkinson's disease (PD) PARK7. DJ-1 plays roles in transcriptional regulation and in oxidative stress function, and its oxidative state at cysteine residues determines activities of DJ-1. In this study, we found that recombinant DJ-1 expressed in and purified from E. coli was specifically cleaved between glycine and proline at amino acid numbers 157 and 158, respectively, by treatment of DJ-1 with H2O2. A substitution mutant of DJ-1 from cysteine to serine at amino acid number 106, a major oxidation site of DJ-1, was found not to be cleaved under an oxidative condition, suggesting oxidation-dependent cleavage of DJ-1. Cleavage of DJ-1 was also observed in human SH-SY5Y cells that had been treated with H2O2. These results suggest that oxidative stress-induced cleavage of DJ-1 regulates functions of DJ-1.
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PMID:Specific cleavage of DJ-1 under an oxidative condition. 1693 23

Loss-of-function mutations in the human PARK7 gene, encoding DJ-1, are a rare cause of autosomal recessive Parkinson's disease (ARPD). To facilitate generation of a novel vertebrate model, in which to examine the biochemical functions of DJ-1 in vivo, we cloned and characterized the zebrafish orthologue of DJ-1 (zDJ-1). The 0.95 kb zDJ-1 mRNA is expressed in adult zebrafish brain, muscle and gut, and in the embryo from 24 h post-fertilization. The zDJ-1 transcript encodes a 19.8 kDa, 189 amino acid protein, which is 83% identical to human DJ-1. Residues thought to be functionally important sites of post-translational modification in human DJ-1, and critical positions affected by pathogenic missense mutations in ARPD patients, are conserved in zDJ-1. The 14 kb zDJ-1 gene contains six exons and is located on zebrafish chromosome 8; the structure of the gene is highly homologous to human DJ-1, except that there are no alternatively spliced non-coding 5' exons. The single zDJ-1 first exon shows 5' end heterogeneity, reflecting multiple transcription start sites. In the adult zebrafish brain, zDJ-1 immunoreactivity was prominent in the cytoplasm of most neurons, and in the neuropil, but was less evident within white matter tracts, consistent with neuronal somatic and dendritic localization. Dopaminergic neurons in each of the major forebrain and diencephalic TH-positive cell groups expressed zDJ-1. These studies show that zDJ-1 is very similar to human DJ-1 and delineate essential resources, allowing further examination of the function and regulation of DJ-1, using the zebrafish as a model.
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PMID:Zebrafish DJ-1 is evolutionarily conserved and expressed in dopaminergic neurons. 1694 55

Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD.
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PMID:Mutations in DJ-1 are rare in familial Parkinson disease. 1699 64

In Parkinson's disease (PD) there is a selective loss of certain midbrain dopaminergic (DA) neurons. The most vulnerable neurons reside in the substantia nigra zona compacta (SNC), whereas the DA neurons in the ventral tegmental area (VTA) and interfascicular (IF) nucleus are less vulnerable to degeneration. Many sporadic PD patients have a defect in mitochondria respiration, and some of the genes that cause PD are mitochondrial-related (e.g., PINK1, Parkin, DJ1). The present study sought to determine whether mitochondria mass is different in SNC neurons compared to other midbrain DA neurons and to non-DA neurons in the mouse. At the electron microscopic level, mitochondria in the SN DA neurons occupy 40% less of the soma and dendritic area than in the SN non-DA neurons. The area occupied by mitochondria in the SN DA neurons is also lower than in the VTA neurons, although not different from the IF neurons. The red nucleus somata have the largest percentage of the somata occupied by mitochondria (12%). Mitochondria size is related to somata size; the largest mitochondria are found in the red nucleus neurons and the smallest mitochondria are found in the IF neurons. At the light microscopic level, SNC, VTA and IF DA neurons have <50% of the cytoplasm immunostained with the mitochondrial antibody 1D6, whereas non-DA neurons in the same midbrain regions contain mitochondria areas up to >65% of the cytoplasm area. These data indicate that mitochondria size and mass are not the same for all neurons, and the SNC DA neurons have relatively low mitochondria mass. The low mitochondria mass in SNC DA neurons may contribute to the selective vulnerability of these neurons in certain rodent models of PD.
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PMID:Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease. 1701 Sep 72

DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses. However, the functional basis of this protection has remained elusive. We found that loss of DJ-1 leads to deficits in NQO1 [NAD(P)H quinone oxidoreductase 1], a detoxification enzyme. This deficit is attributed to a loss of Nrf2 (nuclear factor erythroid 2-related factor), a master regulator of antioxidant transcriptional responses. DJ-1 stabilizes Nrf2 by preventing association with its inhibitor protein, Keap1, and Nrf2's subsequent ubiquitination. Without intact DJ-1, Nrf2 protein is unstable, and transcriptional responses are thereby decreased both basally and after induction. This effect of DJ-1 on Nrf2 is present in both transformed lines and primary cells across human and mouse species. DJ-1's effect on Nrf2 and subsequent effects on antioxidant responses may explain how DJ-1 affects the etiology of both cancer and PD, which are seemingly disparate disorders. Furthermore, this DJ-1/Nrf2 functional axis presents a therapeutic target in cancer treatment and justifies DJ-1 as a tumor biomarker.
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PMID:DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. 1701 34

DJ-1 has multiple functions and its dysfunction may be linked to the onset of familial Parkinson's disease PARK7. However, the function and distribution of DJ-1 is unclear. In this study, we determined DJ-1 distribution and change after intranigral injection of 6-hydroxydopamine (6-OHDA). Although distribution of DJ-1 immunoreactivity was not changed in cerebral cortex and striatum, 6-OHDA caused increase of DJ-1 in the particulate fraction and decrease in the cytosolic fraction in substantia nigra. At that time, DJ-1 shifted to acid forms. These results suggest that distributional changes, translocation, and acidic shift of DJ-1 may be compensatory responses to protect against 6-OHDA-induced oxidative stress.
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PMID:Distribution of DJ-1, Parkinson's disease-related protein PARK7, and its alteration in 6-hydroxydopamine-treated hemiparkinsonian rat brain. 1703 3

The PARK7 gene encodes a protein, DJ-1, with several functions such as protection of cells from oxidative stress, sperm maturation and fertilization and chaperone activity. Mutations in the PARK7 gene are associated with autosomal recessive early-onset Parkinson's disease (Parkinsonism). This work reports the cloning and analysis of the porcine (Sus scrofa) homologue of DJ-1. The porcine PARK7 cDNA was amplified by reverse transcriptase polymerase chain reaction (RT-PCR) using oligonucleotide primers derived from in silico sequences. The porcine PARK7 cDNA (SsPARK7) encodes a protein of 189 amino acids which shows a very high similarity to bovine (97%), to human (96%) and to canine (95%) DJ-1. Protein structure comparison of human and porcine DJ-1 sequences revealed that amino acid changes were few between the two species and not likely to alter DJ-1 structure and function. Quantitative real-time RT-PCR detection exhibited SsPARK7 mRNA expression in all analyzed porcine tissues, although at different levels. Furthermore, expression analysis showed that SsPARK7 transcripts could be detected early in embryo development in different brain regions. The PARK7 gene was demonstrated to be located on porcine chromosome 6. Single-nucleotide polymorphism (SNP) analysis revealed one SNP in the porcine PARK7 gene, giving rise to a silent mutation in exon 6.
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PMID:Porcine DJ-1: cloning of PARK7 cDNA, sequence comparison, expression analysis and chromosomal localization. 1726 84


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