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PARK7  -  parkinson protein 7

Homo sapiens

 
 
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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

 

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

 

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

 

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

  1. Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. van Duijn, C.M., Dekker, M.C., Bonifati, V., Galjaard, R.J., Houwing-Duistermaat, J.J., Snijders, P.J., Testers, L., Breedveld, G.J., Horstink, M., Sandkuijl, L.A., van Swieten, J.C., Oostra, B.A., Heutink, P. Am. J. Hum. Genet. (2001) [Pubmed]
  2. Differential effects of Parkinson's disease-associated mutations on stability and folding of DJ-1. Görner, K., Holtorf, E., Odoy, S., Nuscher, B., Yamamoto, A., Regula, J.T., Beyer, K., Haass, C., Kahle, P.J. J. Biol. Chem. (2004) [Pubmed]
  3. DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. Takahashi, K., Taira, T., Niki, T., Seino, C., Iguchi-Ariga, S.M., Ariga, H. J. Biol. Chem. (2001) [Pubmed]
  4. The 1.1-A resolution crystal structure of DJ-1, the protein mutated in autosomal recessive early onset Parkinson's disease. Wilson, M.A., Collins, J.L., Hod, Y., Ringe, D., Petsko, G.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  5. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. Zhang, L., Shimoji, M., Thomas, B., Moore, D.J., Yu, S.W., Marupudi, N.I., Torp, R., Torgner, I.A., Ottersen, O.P., Dawson, T.M., Dawson, V.L. Hum. Mol. Genet. (2005) [Pubmed]
  6. DJ-1 binds androgen receptor directly and mediates its activity in hormonally treated prostate cancer cells. Tillman, J.E., Yuan, J., Gu, G., Fazli, L., Ghosh, R., Flynt, A.S., Gleave, M., Rennie, P.S., Kasper, S. Cancer Res. (2007) [Pubmed]
  7. DJ-1 colocalizes with tau inclusions: a link between parkinsonism and dementia. Rizzu, P., Hinkle, D.A., Zhukareva, V., Bonifati, V., Severijnen, L.A., Martinez, D., Ravid, R., Kamphorst, W., Eberwine, J.H., Lee, V.M., Trojanowski, J.Q., Heutink, P. Ann. Neurol. (2004) [Pubmed]
  8. Pathological properties of the Parkinson's disease-associated protein DJ-1 in alpha-synucleinopathies and tauopathies: relevance for multiple system atrophy and Pick's disease. Neumann, M., Müller, V., Görner, K., Kretzschmar, H.A., Haass, C., Kahle, P.J. Acta Neuropathol. (2004) [Pubmed]
  9. The biochemistry of Parkinson's disease. Cookson, M.R. Annu. Rev. Biochem. (2005) [Pubmed]
  10. Without DJ-1, the D2 receptor doesn't play. Borrelli, E. Neuron (2005) [Pubmed]
  11. Mitochondria and dopamine: new insights into recessive parkinsonism. Shen, J., Cookson, M.R. Neuron (2004) [Pubmed]
  12. Pathways to Parkinsonism. Cookson, M.R. Neuron (2003) [Pubmed]
  13. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Meulener, M.C., Xu, K., Thompson, L., Ischiropoulos, H., Bonini, N.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  14. DJ-1 mutations in Parkinson's disease. Healy, D.G., Abou-Sleiman, P.M., Valente, E.M., Gilks, W.P., Bhatia, K., Quinn, N., Lees, A.J., Wood, N.W. J. Neurol. Neurosurg. Psychiatr. (2004) [Pubmed]
  15. Immunocytochemical localization of DJ-1 in human male reproductive tissue. Yoshida, K., Sato, Y., Yoshiike, M., Nozawa, S., Ariga, H., Iwamoto, T. Mol. Reprod. Dev. (2003) [Pubmed]
  16. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Canet-Avilés, R.M., Wilson, M.A., Miller, D.W., Ahmad, R., McLendon, C., Bandyopadhyay, S., Baptista, M.J., Ringe, D., Petsko, G.A., Cookson, M.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. Specific cleavage of DJ-1 under an oxidative condition. Ooe, H., Maita, C., Maita, H., Iguchi-Ariga, S.M., Ariga, H. Neurosci. Lett. (2006) [Pubmed]
  18. DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-onset Parkinson disease. Hedrich, K., Djarmati, A., Schäfer, N., Hering, R., Wellenbrock, C., Weiss, P.H., Hilker, R., Vieregge, P., Ozelius, L.J., Heutink, P., Bonifati, V., Schwinger, E., Lang, A.E., Noth, J., Bressman, S.B., Pramstaller, P.P., Riess, O., Klein, C. Neurology (2004) [Pubmed]
  19. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J.W., Yang, L., Beal, M.F., Vogel, H., Lu, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  20. Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Moore, D.J., Zhang, L., Troncoso, J., Lee, M.K., Hattori, N., Mizuno, Y., Dawson, T.M., Dawson, V.L. Hum. Mol. Genet. (2005) [Pubmed]
  21. Lack of mutations in DJ-1 in a cohort of Taiwanese ethnic Chinese with early-onset parkinsonism. Lockhart, P.J., Bounds, R., Hulihan, M., Kachergus, J., Lincoln, S., Lin, C.H., Wu, R.M., Farrer, M.J. Mov. Disord. (2004) [Pubmed]
  22. Causes of Parkinson's disease: genetics of DJ-1. Abou-Sleiman, P.M., Healy, D.G., Wood, N.W. Cell Tissue Res. (2004) [Pubmed]
  23. Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease. Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., Zhu, Z., Ma, H., Pan, Q., Xia, J.H., Xia, K., Zhang, Z. Hum. Mol. Genet. (2006) [Pubmed]
  24. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities. Shinbo, Y., Niki, T., Taira, T., Ooe, H., Takahashi-Niki, K., Maita, C., Seino, C., Iguchi-Ariga, S.M., Ariga, H. Cell Death Differ. (2006) [Pubmed]
  25. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. Honbou, K., Suzuki, N.N., Horiuchi, M., Niki, T., Taira, T., Ariga, H., Inagaki, F. J. Biol. Chem. (2003) [Pubmed]
  26. DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats. Yanagisawa, D., Kitamura, Y., Inden, M., Takata, K., Taniguchi, T., Morikawa, S., Morita, M., Inubushi, T., Tooyama, I., Taira, T., Iguchi-Ariga, S.M., Akaike, A., Ariga, H. J. Cereb. Blood Flow Metab. (2008) [Pubmed]
  27. Pathogenetic mechanisms of parkin in Parkinson's disease. Hattori, N., Mizuno, Y. Lancet (2004) [Pubmed]
  28. DJ-1 is present in a large molecular complex in human brain tissue and interacts with alpha-synuclein. Meulener, M.C., Graves, C.L., Sampathu, D.M., Armstrong-Gold, C.E., Bonini, N.M., Giasson, B.I. J. Neurochem. (2005) [Pubmed]
  29. The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. Zhou, W., Zhu, M., Wilson, M.A., Petsko, G.A., Fink, A.L. J. Mol. Biol. (2006) [Pubmed]
  30. Quantitative proteomic analysis of mitochondrial proteins: relevance to Lewy body formation and Parkinson's disease. Jin, J., Meredith, G.E., Chen, L., Zhou, Y., Xu, J., Shie, F.S., Lockhart, P., Zhang, J. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  31. The Parkinson's disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Xu, J., Zhong, N., Wang, H., Elias, J.E., Kim, C.Y., Woldman, I., Pifl, C., Gygi, S.P., Geula, C., Yankner, B.A. Hum. Mol. Genet. (2005) [Pubmed]
  32. DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor. Zhong, N., Kim, C.Y., Rizzu, P., Geula, C., Porter, D.R., Pothos, E.N., Squitieri, F., Heutink, P., Xu, J. J. Biol. Chem. (2006) [Pubmed]
  33. Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7. Bonifati, V., Dekker, M.C., Vanacore, N., Fabbrini, G., Squitieri, F., Marconi, R., Antonini, A., Brustenghi, P., Dalla Libera, A., De Mari, M., Stocchi, F., Montagna, P., Gallai, V., Rizzu, P., van Swieten, J.C., Oostra, B., van Duijn, C.M., Meco, G., Heutink, P. Neurol. Sci. (2002) [Pubmed]
  34. DJBP: a novel DJ-1-binding protein, negatively regulates the androgen receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by abrogation of this complex. Niki, T., Takahashi-Niki, K., Taira, T., Iguchi-Ariga, S.M., Ariga, H. Mol. Cancer Res. (2003) [Pubmed]
  35. Parkinson's disease: piecing together a genetic jigsaw. Dekker, M.C., Bonifati, V., van Duijn, C.M. Brain (2003) [Pubmed]
  36. Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death. Junn, E., Taniguchi, H., Jeong, B.S., Zhao, X., Ichijo, H., Mouradian, M.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  37. Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Hering, R., Strauss, K.M., Tao, X., Bauer, A., Woitalla, D., Mietz, E.M., Petrovic, S., Bauer, P., Schaible, W., Müller, T., Schöls, L., Klein, C., Berg, D., Meyer, P.T., Schulz, J.B., Wollnik, B., Tong, L., Krüger, R., Riess, O. Hum. Mutat. (2004) [Pubmed]
  38. PARK7 and nucleoside diphosphate kinase A as plasma markers for the early diagnosis of stroke. Allard, L., Burkhard, P.R., Lescuyer, P., Burgess, J.A., Walter, N., Hochstrasser, D.F., Sanchez, J.C. Clin. Chem. (2005) [Pubmed]
 
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