Oxidative Status of DJ-1-dependent Activation of Dopamine Synthesis through Interaction of Tyrosine Hydroxylase and 4-Dihydroxy-l-phenylalanine (l-DOPA) Decarboxylase with DJ-1

Abstract

Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-l-phenylalanine decarboxylase (DDC). DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H2O2, 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO2H and SO3H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. Parkinson disease (PD) is caused by loss of dopamine, which is synthesized from tyrosine by two enzymes, tyrosine hydroxylase (TH) and 4-dihydroxy-l-phenylalanine decarboxylase (DDC). DJ-1 is a causative gene for the familial form of PD, but little is known about the roles of DJ-1 in dopamine synthesis. In this study, we found that DJ-1 directly bound to TH and DDC and positively regulated their activities in human dopaminergic cells. Mutants of DJ-1 found in PD patients, including heterozygous mutants, lost their activity and worked as dominant-negative forms toward wild-type DJ-1. When cells were treated with H2O2, 6-hydroxydopamine, or 1-methyl-4-phenylpyridinium, changes in activities of TH and DDC accompanied by oxidation of cysteine 106 of DJ-1 occurred. It was found that DJ-1 possessing Cys-106 with SH and SOH forms was active and that DJ-1 possessing Cys-106 with SO2H and SO3H forms was inactive in terms of stimulation of TH and DDC activities. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. Parkinson disease (PD) 2The abbreviations used are: PDParkinson diseaseH2O2hydrogen peroxideTHtyrosine hydroxylaseDDCl-DOPA decarboxylaseRT-PCRreverse transcription-PCRGSTglutathione S-transferase6-OHDA6-hydroxydopamineMPP+1-methyl-4-phenylpyridiniuml-DOPA4-dihydroxy-l-phenylalanineGPDHglycerol-3-phosphate dehydrogenaseMALDI-TOFmatrix-assisted laser desorption ionization time-of-flightMSmass spectrometryHPLChigh pressure liquid chromatography. is a neurodegenerative disease that occurs by reduction of the dopamine level through dopaminergic cell death in the substantia nigra. Genetic and environmental factors are thought to be triggers for the onset of PD, but the precise molecular mechanisms are still not known. Dopamine is synthesized by the following two steps: tyrosine is converted to l-DOPA by tyrosine hydroxylase (TH) and then l-DOPA is converted to dopamine by l-dopa decarboxylase (DDC). TH is therefore a key enzyme for dopamine synthesis and is used as a marker for dopaminergic neurons. Parkinson disease hydrogen peroxide tyrosine hydroxylase l-DOPA decarboxylase reverse transcription-PCR glutathione S-transferase 6-hydroxydopamine 1-methyl-4-phenylpyridinium 4-dihydroxy-l-phenylalanine glycerol-3-phosphate dehydrogenase matrix-assisted laser desorption ionization time-of-flight mass spectrometry high pressure liquid chromatography. DJ-1 was first identified by our group as a novel candidate of the oncogene that transformed mouse NIH3T3 cells in cooperation with activated ras (1Nagakubo D. Taira T. Kitaura H. Ikeda M. Tamai K. Iguchi-Ariga S.M. Ariga H. Biochem. Biophys. Res. Commun. 1997; 231: 509-513Crossref PubMed Scopus (667) Google Scholar). Deletion and point (L166P) mutations of DJ-1 have been shown to be responsible for onset of familial Parkinson disease, PARK7 (2Bonifati V. Rizzu P. van Baren M.J. Schaap O. Breedveld G.J. Krieger E. Dekker M.C. Squitieri F. Ibanez P. Joosse M. van Dongen J.W. Vanacore N. van Swieten J.C. Brice A. Meco G. van Duijn C.M. Oostra B.A. Heutink P. Science. 2003; 299: 256-259Crossref PubMed Scopus (2261) Google Scholar), and other homozygous and heterozygous mutations of DJ-1 have been identified in patients with familial or sporadic Parkinson disease (3Abou-Sleiman P.M. Healy D.G. Quinn N. Lees A.J. Wood N.W. Ann. Neurol. 2003; 54: 283-286Crossref PubMed Scopus (328) Google Scholar, 4Hague S. Rogaeva E. Hernandez D. Gulick C. Singleton A. Hanson M. Johnson J. Weiser R. Gallardo M. Ravina B. Gwinn-Hardy K. Crawley A. St. George-Hyslop P.H. Lang A.E. Heutink P. Bonifati V. Hardy J. Singleton A. Ann. Neurol. 2003; 54: 271-274Crossref PubMed Scopus (212) Google Scholar, 5Hedrich K. Djarmati A. Schäfer N. Hering R. Wellenbrock C. Weiss P.H. Hilker R. Vieregge P. Ozelius L.J. Heutink P. Bonifati V. Schwager E. Lang A.E. Noth J. Bressman S.B. Pramstaller P.P. Riess O. Klein C. Neurology. 2004; 62: 389-394Crossref PubMed Scopus (179) Google Scholar, 6Annesi G. Savettieri G. Pugliese P. D'Amelio M. Tarantino P. Ragonese P. La Bella V. Piccoli T. Civitelli D. Annesi F. Fierro B. Piccoli F. Arabia G. Caracciolo M. Cirò Candiano I.C. Quattrone A. Ann. Neurol. 2005; 58: 803-807Crossref PubMed Scopus (141) Google Scholar). DJ-1 is a multifunctional protein and plays roles in transcriptional regulation and anti-oxidative stress function, and loss of its functions is thought to lead to the onset of Parkinson disease and cancer. DJ-1 has three cysteine residues at positions 46, 53, and 106 (Cys-46, Cys-53, and Cys-106, respectively), and these cysteine residues are oxidized after cells receive oxidative stress, resulting in scavenging of reactive oxidative species (7Taira T. Saito Y. Niki T. Iguchi-Ariga S.M. Takahashi K. Ariga H. EMBO Rep. 2004; 5: 213-218Crossref PubMed Scopus (751) Google Scholar, 8Kinumi T. Kimata J. Taira T. Ariga H. Niki E. Biochem. Biophys. Res. Commun. 2004; 317: 722-728Crossref PubMed Scopus (307) Google Scholar, 9Canet-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; 101: 9103-9108Crossref PubMed Scopus (917) Google Scholar, 10Martinat C. Shendelman S. Jonason A. Leete T. Beal M.F. Yang L. Floss T. Abeliovich A. PLoS Biol. 2004; 2: e327Crossref PubMed Scopus (248) Google Scholar, 11Inden M. Taira T. Kitamura Y. Yanagida T. Tsuchiya D. Takata K. Yanagisawa D. Nishimura K. Taniguchi T. Kiso Y. Yoshimoto K. Agatsuma T. Koide-Yoshida S. Iguchi-Ariga S.M. Shimohama S. Ariga H. Neurobiol. Dis. 2006; 24: 144-158Crossref PubMed Scopus (168) Google Scholar, 12Yanagida T. Tsushima J. Kitamura Y. Yanagisawa D. Takata K. Shibaike T. Yamamoto A. Taniguchi T. Yasui H. Taira T. Morikawa S. Inubushi T. Tooyama I. Ariga H. Oxid. Med. Cell Long. 2009; 1: 36-42Crossref Scopus (69) Google Scholar). Although DJ-1 does not directly bind to DNA, DI-1 acts as a co-activator to activate various transcription factors, including the androgen receptor and p53 tumor suppressor, PSF and Nrf2, by their factors K. Taira T. Niki T. C. Iguchi-Ariga S.M. Ariga H. J. Biol. PubMed Scopus Google Scholar, T. K. Taira T. Iguchi-Ariga S.M. Ariga H. Res. 2003; 1: Google Scholar, Y. Taira T. Niki T. Iguchi-Ariga S.M. Ariga H. J. 2005; Google Scholar, N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar, C.M. Proc. Natl. Acad. Sci. U.S.A. 2006; PubMed Scopus Google Scholar, J. G. L. R. M. S. Res. PubMed Scopus Google Scholar). anti-oxidative stress of DJ-1 is therefore thought to be by of cysteine residues and by of It has been that a transcription to the of the TH gene to its and that human DJ-1 to PSF to the to of TH gene in human cells N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar). have shown that of DJ-1 the substantia of PD in which dopaminergic cell death was by of 6-hydroxydopamine, cell death and and dopamine of the that DJ-1 dopamine M. Taira T. Kitamura Y. Yanagida T. Tsuchiya D. Takata K. Yanagisawa D. Nishimura K. Taniguchi T. Kiso Y. Yoshimoto K. Agatsuma T. Koide-Yoshida S. Iguchi-Ariga S.M. Shimohama S. Ariga H. Neurobiol. Dis. 2006; 24: 144-158Crossref PubMed Scopus (168) Google Scholar). has not been DJ-1 the of or activity of that are to dopamine In this study, we found that DJ-1 directly to TH and DDC to their activities. Mutants of DJ-1 found in PD patients lost their activity to TH and and stimulation in a the oxidative of Cys-106 of wild-type DJ-1. These findings indicate an essential role of DJ-1 in dopamine synthesis and contribution of DJ-1 to the sporadic form of PD. of cells with of the DJ-1 gene and cells a was S. Yanagida T. K. S. M. Kitamura Y. S. Taira T. K. M. Iguchi-Ariga S.M. Ariga H. J. PubMed Scopus Google Scholar). cells and these cell were in with wild-type or was cells by the and the cells were in a in the of for to the were then and of was by with an of the used for and were as human DJ-1 and human DJ-1 human TH and human TH human DDC and human DDC human and human human DJ-1 and human DJ-1 human TH and human TH human DDC and human DDC and human and human were from cells and to and as T. Kitaura H. Y. T. Iguchi-Ariga S.M. Ariga H. Cell Res. PubMed Scopus Google Scholar). the of in were from cells with a and were then a and to with the were with an or and by an used were TH with a at and was by as (1Nagakubo D. Taira T. Kitaura H. Ikeda M. Tamai K. Iguchi-Ariga S.M. Ariga H. Biochem. Biophys. Res. Commun. 1997; 231: 509-513Crossref PubMed Scopus (667) Google Scholar). TH and DDC were synthesized in the of the were with or in and from at for in a and with the the bound were in a and by were from cells by the K. Taira T. Niki T. C. Iguchi-Ariga S.M. Ariga H. J. Biol. PubMed Scopus Google Scholar). were with an or and the were by with an or the mouse as of the human TH gene was by and from human cells as of used for are as human TH and human TH of the human TH gene was with and and were and of was cells in a were with of and various of with of by the van A.J. PubMed Scopus Google Scholar). after cell was by of from the gene to the cells. a of the was used for the to the as K. Y. Kitaura H. Taira T. Iguchi-Ariga S.M. Ariga H. J. Biol. PubMed Scopus Google Scholar), and the activity to the was a in of the cell were by with an and as were three TH and DDC activities in cells were to the N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar, R. J. 2006; PubMed Scopus Google Scholar). and used were and the used was a and were from cells with a and of was with l-DOPA decarboxylase for or l-DOPA for and various of at for and the was by of of the at for the was through a and to as Cell from cells were as and with a of and were a the been with a to DJ-1 was with a and with were with and a of the were an in and with was with the of were with and with mouse and mouse cells were with cells were then with a or an and a are as were of by the of DJ-1 and activity of TH and human in which the DJ-1 gene was were by of a human as S. Yanagida T. K. S. M. Kitamura Y. S. Taira T. K. M. Iguchi-Ariga S.M. Ariga H. J. PubMed Scopus Google Scholar), and were S. Yanagida T. K. S. M. Kitamura Y. S. Taira T. K. M. Iguchi-Ariga S.M. Ariga H. J. PubMed Scopus Google Scholar). cells the were and of DJ-1 and TH in DJ-1 and cells were by was used as a N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar), the level of TH in DJ-1 cells was after DJ-1 been by to to the level of DJ-1 in or cells were and reduction of TH gene in DJ-1 cells were the other and that of the DDC gene in DJ-1 cells was not and to the of TH and DDC the protein of TH and DDC were found to be and not to be in DJ-1 cells by and TH and DDC activities in DJ-1 cells were then Although TH activity was DDC activity was found to be and as for cells were human cells were used not of TH and DDC activities in DJ-1 cells was caused by or by of enzymes, TH and DDC activities were by the of TH and DDC and that TH and DDC activities are in DJ-1 that a other transcriptional regulation of the DDC gene by DJ-1 is responsible for the activity of DDC in DJ-1 cells. from cells were with an and and were by with and that TH and DDC were with of DJ-1 with TH and with DDC and the of DJ-1 with TH and DDC is or were these or was with TH or DDC that been synthesized in a that but not bound to TH and of DJ-1 with TH and with DDC and cells were then with and or with and and DJ-1 and TH or DDC were by and of of DJ-1 with TH and with DDC in cells and It was found that were or DJ-1 and TH and DJ-1 and of DJ-1 with TH and with a and TH was cells. after from cells were with an or with and of the were by with and other of the was with a and were with an by DDC and DJ-1 were with the that was with DDC or with DJ-1. of with and DDC and a and DDC in cells. in which or was with DDC that been synthesized in were to the of TH with that but not bound to of TH with DDC then the of DJ-1 TH and DDC activities. and were with from which are enzyme for TH and in the of tyrosine or for TH and and the of l-DOPA or dopamine was and that but not TH and DDC activities in a the of this protein were first with an or and TH and DDC activities were then in the of that the or but not the enzyme activities and When from DJ-1 cells were used as enzyme TH and DDC activities from cells were in the of various of in to DJ-1 in protein from cells enzyme activities of TH and DDC and the of DJ-1 activities of or from cells were with or and to and were then of the and were found to bind to this and of TH or DDC were as and When activities of and forms of TH and DDC were was found that wild-type TH and DDC high activities but that TH and DDC or TH and DDC or and These that of DJ-1 to TH and DDC their activities. is known that the activity of TH is by its the level of TH at in the used in the for which are shown in was in the level of TH was that DJ-1 TH activity of TH protein mutations in the DJ-1 gene have been found in PD patients TH or DDC activity is to be we the of mutations of DJ-1 TH and DDC activities. and DJ-1 are from homozygous and and DJ-1 are from heterozygous mutations of the DJ-1 oxidation of DJ-1 at Cys-106 is for DJ-1 to its functions K. Niki T. Taira T. Iguchi-Ariga S.M. Ariga H. Biochem. Biophys. Res. Commun. 2004; PubMed Scopus Google Scholar), DJ-1 was first activities of these DJ-1 to TH or DDC by in of the and wild-type DJ-1 were found to bind to TH and were in activity of DJ-1 to TH and DDC and of DJ-1 TH and DDC activities were then the in Although wild-type DJ-1 TH activity to TH was not by of the in which of DJ-1 was to of the DJ-1 activity that been by wild-type DJ-1 in a It is that the of DJ-1 as that of wild-type DJ-1 was in the activity of of that by wild-type DJ-1 was in which of wild-type and of DJ-1 was that of the mutants, from heterozygous mutations of the DJ-1 as a dominant-negative form wild-type DJ-1. In the of the other of the of DJ-1 were found to have activity toward DDC with the activity of wild-type DJ-1 and to the activity of wild-type DJ-1 a dominant-negative the of of DJ-1 TH and DDC activities in cells wild-type and of and were and of DJ-1 and wild-type DJ-1 were by with and and DJ-1 and DJ-1 were found to be that of mouse and wild-type DJ-1 and DJ-1 were at that of mouse DJ-1. the of TH and DDC in these cell were by not and and of in was Although the of DDC in cells wild-type and of DJ-1 were not the of TH in cells wild-type DJ-1 and of DJ-1 were and with the in cells the or cells of TH and DDC were to of their of TH but not DDC were in cells and DJ-1 and of with TH or cell were with an and the were by with an or DDC that of the of DJ-1 bound to TH and TH and DDC activities in these cells were and of their activities to of the in or cells were found in cells of DJ-1 and the of wild-type DJ-1 toward TH and DDC cells were with various of for and DJ-1. two after cells were in the of and DDC or in the of l-DOPA for of DJ-1 and of DJ-1 were then by with and of for of DJ-1 to or that of DJ-1. Although wild-type DJ-1 TH and DDC activities in a and but not were found to TH and DDC activities to of the activities in wild-type cells and a role of of DJ-1 toward TH and oxidation of Cys-106 is for DJ-1 to its function, the oxidative of Cys-106 in cells to H2O2, 6-hydroxydopamine and 1-methyl-4-phenylpyridinium was and are and are known to dopaminergic cell death in cells and cells were to various of H2O2, or for and then or l-DOPA was for TH or DDC after of or the cells were and used for of the oxidative of Cys-106, of and and activities of TH and the oxidative of Cys-106, from cells were with an and were a protein to DJ-1 was with and to oxidative stress, of Cys-106 of DJ-1 was a and this form was in a accompanied by an in SO2H and SO3H forms after cells were to H2O2, and these of of TH and DJ-1 were by not and and that of DJ-1 was with of H2O2, and and at the of TH a at and was then activity of the TH gene was this cells were with a the to from the transcriptional of the human TH after cells were to various of H2O2, and for and their activity was that activity a to that of of the TH of of and DJ-1 were by that the level of DDC was not of cells with the three the TH level first to of and then as in the of TH level When TH activities in cells to H2O2, and were to of and protein were TH activity was at of and then to a level that Although of DDC and protein were not the of cells to activity of DDC TH a the of the of oxidative activity of DJ-1 to TH and cells were treated with various of H2O2, and for and the activity of glycerol-3-phosphate dehydrogenase which does not bind to was cells that been with an and for wild-type DJ-1 or of DJ-1 were treated with for at after and then activity was of These that and of TH and DDC activities with the oxidative of Cys-106 of DJ-1. directly this DJ-1 was to and then to of DJ-1 were used for of the oxidative of Cys-106 and for its activity toward TH and DDC activities in of the DJ-1 a form of Cys-106, and the of SH and SOH forms was of of DJ-1 with for the of the SOH form but the of the SH and SOH forms of Cys-106 was still of of DJ-1 with and for the of the SH and SOH forms of Cys-106 to and and forms with SO2H and SO3H to of forms TH and DDC activity the other were high DJ-1 was treated with and for and were lost with that DJ-1 possessing Cys-106 with SH and SOH forms is active and that DJ-1 possessing Cys-106 with SO2H and SO3H forms is inactive in terms of stimulation of TH and DDC and that DJ-1 possessing Cys-106 with SO2H and SO3H forms acts as a dominant-negative form active DJ-1. of TH with DJ-1 or with DDC in cells that been treated with was then cells TH were treated with and for and in cell were with an by of protein were and activity of DJ-1 or DDC to TH is shown that the of of DJ-1 with TH or that of DDC with TH was in a These that a protein and DDC was oxidative stress oxidation of Cys-106 of DJ-1 the activity of DJ-1 toward TH and In this study, we that DJ-1 that are in dopamine synthesis in human cells through of DJ-1 with TH and Although of DJ-1 found in patients with familial and sporadic forms of PD, wild-type bound to TH and the activities of these were and worked as a dominant-negative form wild-type DJ-1. we found that the activity of DJ-1 the of the and SOH forms of Cys-106, which for of Although mechanisms of DJ-1 and oxidized DJ-1 TH and DDC are not is that the of wild-type which is for DJ-1 to TH and DDC is by or by resulting in loss of its It has been that DJ-1 transcription of the TH gene by a for TH gene through its N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar). have but transcription of the DDC gene was not by DJ-1 DJ-1 therefore TH activity by of TH gene and by and DJ-1 DDC activity by of of TH by various TH activity C. T. M. T. N. T. S. H. T. T. PubMed Scopus Google Scholar, C. J. D.G. B. J. J. P. J. Biochem. PubMed Scopus Google Scholar, K. R. P. J. J. PubMed Scopus Google Scholar, J. H. J. Biol. 2009; PubMed Scopus Google Scholar). of DJ-1 in and in not of its activity was and that DJ-1 TH activity of It has been that was with DDC and DDC activity in dopaminergic cells R. J. 2006; PubMed Scopus Google Scholar). DJ-1 of N. Rizzu P. C. Squitieri F. Heutink P. J. J. Biol. 2006; PubMed Scopus Google Scholar), is that DJ-1 and their functions in dopamine synthesis. Although of TH and DDC and their activities in PD patients DJ-1 mutations have not been the level of dopamine and dopaminergic cell death in these patients be and In DJ-1 the other dopaminergic cell death not resulting in reduction of dopamine A. M. T. C. Y. G. A. A. G. P. J. 2005; PubMed Scopus Google Scholar, H. S. S. A. A.J. P. D. H. Proc. Natl. Acad. Sci. U.S.A. 2005; PubMed Scopus Google Scholar, L. B. T. S. Y. P.M. J. Biol. 2005; PubMed Scopus Google Scholar). and dopaminergic in DJ-1 have been L. B. T. S. Y. P.M. J. Biol. 2005; PubMed Scopus Google Scholar). reduction of and activities of TH and DDC in DJ-1 not these in and found that DJ-1 transcription of the human TH gene but not the mouse TH gene not be of the for these In cells of DJ-1 found in PD patients, the level of the TH but not that of the DDC was loss of transcriptional activity of of DJ-1. Although these bound to TH and activities of TH and DDC were the dominant-negative of heterozygous mutants, and wild-type DJ-1 TH and DDC activities that heterozygous of the DJ-1 gene onset of PD, is a in familial PD. stress is thought to be a of PD. of the form of DJ-1 and the of oxidized DJ-1 have been found in of patients with PD R. A.E. Cookson M.R. T. R. Miller D.W. McLendon C. C. A.J. P.M. Healy D.G. Ariga H. Wood N.W. R. T. Hardy Lees A.J. 2004; PubMed Scopus Google Scholar), and of oxidized DJ-1 has been found in patients with Parkinson disease and in patients with disease J. M.C. M. L. J. Biol. 2006; PubMed Scopus Google Scholar). the three cysteine residues of Cys-106 is the to oxidative stress and is oxidized as and SO3H T. Kimata J. Taira T. Ariga H. Niki E. Biochem. Biophys. Res. Commun. 2004; 317: 722-728Crossref PubMed Scopus (307) Google Scholar). M. Wilson M.A. Petsko G.A. J. Biol. 2006; PubMed Scopus Google has that DJ-1 at Cys-106 with SO2H is an active form in terms of activity toward of oxidized form of Cys-106 of DJ-1 not found that the level of the TH gene was first and then in a in cells that been treated with H2O2, and that transcriptional activity of DJ-1 its oxidative to transcriptional activity of the activity of DJ-1 toward TH and DDC a and that the activity of DJ-1 the of the and SOH forms of Cys-106, which for of and DDC was and of TH with DJ-1 or with DDC was with in the of to which cells were and of an inactive in cells an oxidative stress sporadic form of PD is an disease, and oxidation of DJ-1 in and has been M.C. K. L. L. H. Proc. Natl. Acad. Sci. U.S.A. 2006; PubMed Scopus Google Scholar). It is therefore thought that of DJ-1 with the dopamine synthesis to the onset of PD. oxidative stress of DJ-1 has been by and other (7Taira T. Saito Y. Niki T. Iguchi-Ariga S.M. Takahashi K. Ariga H. EMBO Rep. 2004; 5: 213-218Crossref PubMed Scopus (751) Google Scholar, 9Canet-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; 101: 9103-9108Crossref PubMed Scopus (917) Google Scholar, 10Martinat C. Shendelman S. Jonason A. Leete T. Beal M.F. Yang L. Floss T. Abeliovich A. PLoS Biol. 2004; 2: e327Crossref PubMed Scopus (248) Google Scholar, 11Inden M. Taira T. Kitamura Y. Yanagida T. Tsuchiya D. Takata K. Yanagisawa D. Nishimura K. Taniguchi T. Kiso Y. Yoshimoto K. Agatsuma T. Koide-Yoshida S. Iguchi-Ariga S.M. Shimohama S. Ariga H. Neurobiol. Dis. 2006; 24: 144-158Crossref PubMed Scopus (168) Google Scholar), and DJ-1 have been shown to be to oxidative A. M. T. C. Y. G. A. A. G. P. J. 2005; PubMed Scopus Google Scholar, H. S. S. A. A.J. P. D. H. Proc. Natl. Acad. Sci. U.S.A. 2005; PubMed Scopus Google Scholar, L. B. T. S. Y. P.M. J. Biol. 2005; PubMed Scopus Google Scholar, E. C. L. B. B. M. H. S. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). the that functions of DJ-1 in terms of oxidative stress and dopamine synthesis to the of Parkinson and for their with