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
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
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DOI：
10.1074/jbc.m109.019950
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发表时间：
2009-10-16
影响因子：
4.8
通讯作者：
Iguchi-Ariga, Sanae M. M.
中科院分区：
文献类型：
--
作者：
Ishikawa, Shizuma;Taira, Takahiro;Iguchi-Ariga, Sanae M. M.
帕金森病(PD)是由酪氨酸通过酪氨酸羟基酶(TH)和4-二羟基-L-苯丙氨酸脱羧酶(DDC)两种酶合成的多巴胺引起的。DJ-1是家族性帕金森病的致病基因，但对其在多巴胺合成中的作用知之甚少。在这项研究中，我们发现DJ-1直接与TH和DDC结合，并正向调节它们在人多巴胺能细胞中的活性。在帕金森病患者中发现的DJ-1突变株，包括杂合子突变株，失去了活性，并对野生型DJ-1起显性-阴性作用。细胞经H_2O_2、6-羟基多巴胺或1-甲基-4-苯基吡啶处理后，DJ-1的TH和DDC活性发生变化，同时伴有半胱氨酸106的氧化。结果表明，具有SH和SOH形式的Cys-106的DJ-1对TH和DDC活性的刺激作用较弱。这些发现表明DJ-1在多巴胺合成中起重要作用，并在散发性帕金森病中起重要作用。
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.