Salazar Julio, Mena Natalia, Hunot Stephane, Prigent Annick, Alvarez-Fischer Daniel, Arredondo Miguel, Duyckaerts Charles, Sazdovitch Veronique, Zhao Lin, Garrick Laura M, Nuñez Marco T, Garrick Michael D, Raisman-Vozari Rita, Hirsch Etienne C
Institut National de la Santé et de la Recherche Médicale, Neurologie et Thérapeutique Expérimentale, Unité Mixte de Recherche S679, 47 Boulevard de l'Hôpital, 75013 Paris, France.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18578-83. doi: 10.1073/pnas.0804373105. Epub 2008 Nov 14.
Dopaminergic cell death in the substantia nigra (SN) is central to Parkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.
黑质（SN）中的多巴胺能细胞死亡是帕金森病（PD）的核心问题，但神经退行性变机制尚未完全阐明。PD患者SN中多巴胺能细胞和胶质细胞内的铁蓄积可能导致氧化应激、蛋白质聚集及神经元死亡。铁蓄积所涉及的机制也仍不清楚。在此，我们描述了PD患者SN中二价金属转运体1（DMT1/Nramp2/Slc11a2）一种亚型的表达增加。利用小鼠1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒的PD动物模型，我们发现中毒动物腹侧中脑的DMT1表达增加，同时伴有铁蓄积、氧化应激及多巴胺能细胞丢失。此外，我们报道DMT1中一个损害铁转运的突变可保护啮齿动物免受帕金森病诱导神经毒素MPTP和6-羟基多巴胺的影响。本研究支持DMT1在PD铁介导的神经退行性变中起关键作用。
