Tyrosine hydroxylase and Parkinson's disease
Tyrosine hydroxylase and Parkinson's disease
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DOI：
10.1007/bf02741387
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发表时间：
1998-06-01
影响因子：
5.1
通讯作者：
Toska, Karen
中科院分区：
文献类型：
--
作者：
Haavik, Jan;Toska, Karen
帕金森病（PD）中一个一致的神经化学异常是黑质多巴胺能神经元变性，导致纹状体多巴胺（DA）水平降低。由于酪氨酸羟化酶（TH）催化DA生物合成中的限速步骤--l-多巴的形成，因此该疾病可被认为是纹状体TH缺乏综合征。类似地，一些患有遗传性多巴反应性肌张力障碍（一种与PD具有临床相似性的神经系统疾病）的患者具有TH基因突变和TH活性和/或稳定性降低。因此，PD的逻辑和有效的治疗策略是基于通过用1-DOPA、DA激动剂、DA代谢抑制剂或具有表达TH的细胞的脑移植物治疗来纠正或绕过酶缺乏。TH的直接致病作用也已被提出，因为该酶是体外活性氧（ROS）的来源和自由基介导的氧化损伤的靶点。最近，它已被证明，l-多巴是有效的氧化哺乳动物TH在体外，可能有助于多巴的细胞毒性作用。因此，这种酶可能在几个不同的水平参与PD的发病机制，除了是一个有前途的候选人，为开发新的治疗这种疾病。
A consistent neurochemical abnormality in Parkinson's disease (PD) is degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation ofl-DOPA, the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Similarly, some patients with hereditaryl-DOPA-responsive dystonia, a neurological disorder with clinical similarities to PD, have mutations in the TH gene and decreased TH activity and/or stability. Thus, a logical and efficient treatment strategy for PD is based on correcting or bypassing the enzyme deficiency by treatment withl-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing TH. A direct pathogenetic role of TH has also been suggested, as the enzyme is a source of reactive oxygen species (ROS) in vitro and a target for radical-mediated oxidative injury. Recently, it has been demonstrated thatl-DOPA is effectively oxidized by mammalian TH in vitro, possibly contributing to the cytotoxic effects of DOPA. This enzyme may therefore be involved in the pathogenesis of PD at several different levels, in addition to being a promising candidate for developing new treatments of this disease.