Poly(ABP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism
Poly(ABP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism
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DOI：
10.1073/pnas.96.10.5774
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发表时间：
1999-05-11
影响因子：
11.1
通讯作者：
Dawson, TM
中科院分区：
文献类型：
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作者：
Mandir, AS;Przedborski, S;Dawson, TM
l-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是一种导致人类和非人类动物帕金森病的神经毒素，它的使用使人们对帕金森病的发病机制有了更深入的了解。然而，其分子靶点尚未确定。我们发现，缺乏多（ADP-核糖）聚合酶（PARP）基因的小鼠可以显著避免MPTP神经毒性。PARP是在DNA损伤后催化ADP核糖单位从NAD附着到核蛋白上的酶。MPTP有效地激活PARP，只在黑质中含有易受伤害的多巴胺的神经元中。MPTP引发核蛋白的聚（adp -核糖基）化的新模式，完全依赖于神经来源的一氧化氮。因此，NO、DNA损伤和PARP激活在mptp诱导的帕金森病中起关键作用，并提示PARP抑制剂可能在帕金森病的治疗中具有保护作用。
l-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson's disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson's disease.