Disease relevance of PARK7

• Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism [1].
• Mutations in the PARK7/DJ-1 gene cause autosomal-recessive Parkinson's disease [2].
• Later DJ-1 was also found to be an infertility-related protein that was reduced in rat sperm treated with sperm toxicants that cause infertility in rats [3].
• Taken together, the crystal structure of human DJ-1 plus other observations suggest the possible involvement of this protein in the cellular oxidative stress response and a general etiology of neurodegenerative diseases [4].
• To further investigate whether pathogenic mutations might prevent the distribution of DJ-1 to mitochondria, we generated human neuroblastoma cells stably transfected with wild-type (WT) or mutant (M26I, L166P, A104T, D149A) DJ-1 and performed mitochondrial fractionation and confocal co-localization imaging studies [5].
• These data provide a novel mechanism where DJ-1-mediated regulation of AR may promote the progression of prostate cancer to androgen independence [6].

Psychiatry related information on PARK7

• DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia [7].
• Neuronal tau inclusions were DJ-1 immunopositive in Pick's disease (PiD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease [8].

High impact information on PARK7

• In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology [9].
• In this issue of Neuron, Goldberg et al. report of an exciting link between the loss of function of DJ-1, a protein associated with familial parkinsonism, and D2 receptor activity [10].
• Recessively inherited mutations in parkin, DJ-1, and PINK1 have recently been linked to familial forms of parkinsonism [11].
• 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 [12].
• 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 [13].

Chemical compound and disease context of PARK7

• The hypothesis was also tested that young onset Parkinson's disease patients in whom, despite extensive analysis, only a single heterozygous parkin mutation was found, might harbour a second mutation in the DJ-1 gene--that is, digenic inheritance [14].
• DJ-1 was identified as an activated ras-dependent oncogene product, and was also found to be an infertility-related protein (contraception-associated protein 1; CAP 1) that was reduced in rat spermatozoa treated with ornidazole, one of the endocrine disrupting substances that causes reversible infertility in rats [15].
• The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization [16].
• 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 H(2)O(2) [17].

Biological context of PARK7

• DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families [18].
• The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1 [19].
• However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored [20].
• In addition, we developed quantitative polymerase chain reaction assays to examine the genomic copy number of DJ-1 exons [21].
• Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1-5 of the gene and an Italian kindred with a homozygous L166P missense mutation [22].

Anatomical context of PARK7

• Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells [20].
• In ejaculated spermatozoa, DJ-1 existed on the surface of the posterior part of head and the anterior part of the midpiece [15].
• To determine the functions of DJ-1 in the human reproductive system as a target protein of endocrine active substances, we identified the localization of DJ-1 in human testis, epididymis, ejaculated spermatozoa, and seminal plasma [15].
• In contrast to previous findings, we detected DJ-1 in seminal plasma of fertile men [15].
• DJ-1 was present in cells existing in the seminiferous tubules and Leydig cells [15].

Associations of PARK7 with chemical compounds

• A highly conserved cysteine residue, which is catalytically essential in homologues of DJ-1, shows an extreme sensitivity to radiation damage and may be subject to other forms of oxidative modification as well [4].
• We observed a cysteine-sulfinic acid at C106 in crystalline DJ-1 but no modification of C53 or C46 [16].
• Furthermore, co-expression of wild-type DJ-1 and PINK1 suppresses neurotoxin 1-methyl-4-phenylpyridinium (MPP(+))-induced death of dopaminergic SH-SY5Y cells [23].
• Here, we report that DJ-1 was sumoylated on a lysine residue at amino-acid number 130 (K130) by PIASxalpha or PIASy [24].
• DJ-1 has also been identified as a hydroperoxide-responsive protein [25].
• The intrastriatal injection of recombinant glutathione S-transferase-tagged human DJ-1 (GST-DJ-1) markedly reduced infarct size in 2,3,5-triphenyltetrazolium chloride staining at 3 days after MCAO [26].

Physical interactions of PARK7

• Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1 [20].
• Furthermore, DJ-1 might interact with SUMO-1 (small ubiquitin-like modifier), which can counteract ubiquitin and stabilise proteins against degradation by the 26S proteasome [27].
• DJ-1 is present in a large molecular complex in human brain tissue and interacts with alpha-synuclein [28].

Enzymatic interactions of PARK7

• Since the aggregation of alpha-synuclein is believed to be a critical step in the etiology of PD, we have investigated the interaction of wild-type DJ-1 and its oxidized forms with alpha-synuclein [29].

Co-localisations of PARK7

• The results demonstrated that DJ-1 was not only colocalized with alpha-synuclein in dopaminergic neurons but also to cytoplasmic inclusions in mice treated with MPTP/prob [30].

Regulatory relationships of PARK7

• Mutations in genes encoding both DJ-1 and pten-induced kinase 1 (PINK1) are independently linked to autosomal recessive early-onset familial forms of Parkinson's disease (PD) [23].
• Unlike pathogenic DJ-1 mutants, wild-type DJ-1 acts to inhibit the transcriptional silencing activity of the PSF [31].
• The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein [29].
• DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor [32].

Other interactions of PARK7

• These results indicate that DJ-1 is a positive regulator of the androgen receptor [3].
• Recruiting new families will help cloning the defective genes at PARK6 and PARK7 loci [33].
• These results suggest that AR is positively regulated by DJ-1, which antagonizes the function of negative regulators, including DJBP [34].
• The recent identification of the fourth and fifth Parkinson's disease genes suggests multiple pathways-an impaired oxidative stress defence for mutations in DJ-1, and a defect in another signalling pathway for mutations in NR4A2 [35].
• To elucidate the mechanism of this cell-preserving function, we have screened out the death protein Daxx as a DJ-1-interacting partner [36].

Analytical, diagnostic and therapeutic context of PARK7

• To determine the functions of DJ-1, cDNAs encoding DJ-1-binding proteins were screened by the yeast two-hybrid method [3].
• We demonstrate by crystallography that the E64D mutation does not alter the structure of the DJ1 protein, however we observe a tendency towards decreased levels of the mutant protein when overexpressed in HEK293 or COS7 cells [37].
• Using immunocytochemistry in contrast to the homogenous nuclear and cytoplasmic staining in HEK293 cells overexpressing wild-type DJ1, about 5% of the cells expressing E64D and up to 80% of the cells expressing the recently described L166P mutation displayed a predominant nuclear localization of the mutant DJ1 protein [37].
• CONCLUSIONS: PARK7 and NDKA may be useful plasma biomarkers for the early diagnosis of stroke [38].
• METHODS: We used ELISA to measure PARK7 and NDKA in plasma in 3 independent European and North American retrospective studies encompassing a total of 622 stroke patients and 165 control individuals [38].

References