Disease relevance of Park7

• Parkin-deficient animals exhibit mitochondrial degeneration and increased oxidative stress vulnerability, and both mice and flies lacking DJ-1 are hypersensitive to environmental toxins associated with Parkinson's disease (PD) [1].
• We used recombinant adeno-associated virus (AAV) gene transfer to study the influence of DJ-1 and Parkin on the dopaminergic system of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, a model for sporadic PD [1].
• Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism [2].
• Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1 [2].
• Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress [3].

Psychiatry related information on Park7

• Polymorphism in the human DJ-1 gene is not associated with sporadic dementia with Lewy bodies or Parkinson's disease [4].

High impact information on Park7

• Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions [2].
• Although DJ-1(-/-) mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake [2].
• Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1(-/-) mice, but long-term depression (LTD) was absent [2].
• DJ-1/PARK7, a cancer- and Parkinson's disease (PD)-associated protein, protects cells from toxic stresses [5].
• Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes [3].

Chemical compound and disease context of Park7

• Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES- derived cell model of primary Parkinsonism [6].
• We then found that DJ-1 knockdown by short interfering RNA rendered SH-SY5Y neuroblastoma cells susceptible to hydrogen peroxide-, MPP+- or 6-hydroxydopamine-induced cell death and that cells harbouring mutant forms of DJ-1, including L166P, became susceptible to death in parallel with the loss of oxidized forms of DJ-1 [7].

Biological context of Park7

• DJ-1 has been identified as a novel oncogene that transforms mouse NIH3T3 cells in cooperation with activated ras [8].
• Both genomic DNAs comprise 7 exons spanning about 16-24 kb, in which 2-6 exons encode the DJ-1 protein [8].
• The human DJ-1 gene was mapped at chromosome 1p36.2-p36.3, a region that has been shown to be a hot spot of chromosome abnormalities in several tumor cells [8].
• These findings suggest that DJ-1 regulates expressions of genes for which functions are thought to be related to cell death or neurodegeneration [9].
• DJ-1, sharing no significant homology with the sequences so far reported, did not show transactivation activity in the Gal4 recombinant system, but transformed mouse NIH3T3 cells by itself [10].

Anatomical context of Park7

• 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) [11].
• To analyze the promoter of the human DJ-1 gene, a series of deletion constructs of the region upstream of exon 2 were linked to the luciferase gene, and their luciferase activities were measured in human HeLa cells [8].
• Lipopolysaccharide (LPS) significantly increased the expression of DJ-1/5.8 in murine peritoneal macrophages (Mphi) and a murine macrophage cell line (J774) [12].
• The DJ-1 gene does not appear to be a significant risk factor for late onset Lewy body disease in this population [4].
• The high expression of DJ-1 in neuronal and glial cells, that is not confined to a single functional system or any anatomical area, supports the view of a basic physiological role in cell biology [13].

Associations of Park7 with chemical compounds

• However, DJ-1 overexpression also reduced postsynaptic dopamine receptor responses in normal mice [1].
• MPTP drastically reduced dopamine to 19% of normal levels and neither DJ-1 nor Parkin protected against MPTP-induced catecholamine loss under these conditions [1].
• Our results show that Parkin and DJ-1 inhibit dopamine neuron death and enhance amphetamine-induced dopaminergic function in a mouse model of idiopathic PD [1].
• Diphenylene iodonium, a flavoenzyme inhibitor, blocked the effect of LPS on DJ-1/5.8 expression [12].
• DJ-1 was first identified as an activated ras-dependent oncogene product and was later also found to be an infertility-related protein affected by sperm toxicants such as ornidazole (OR) and epichlorohydrin [14].
• Cytoprotective binding of DJ-1 to ASK1 depends on the central redox-sensitive Cys-106 and may be modulated by peripheral cysteine residues [15].

Analytical, diagnostic and therapeutic context of Park7

• These results warrant further exploration of DJ-1 and Parkin gene therapy for PD, although a better understanding of their effects on behavior and dopamine neurotransmission is required before these proteins can be safely used.Molecular Therapy (2007) 15 4, 698-704. doi:10.1038/sj.mt.6300067 [1].
• We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities [3].
• However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine [3].
• However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease [16].
• Molecular cloning of human and mouse DJ-1 genes and identification of Sp1-dependent activation of the human DJ-1 promoter [8].

References