Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice
Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice
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DOI：
10.1523/jneurosci.0970-05.2005
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发表时间：
2005-07-13
影响因子：
5.3
通讯作者：
Przedborski, S
中科院分区：
文献类型：
--
作者：
Choi, DK;Pennathur, S;Przedborski, S
帕金森病（PD）的特征是腹部中脑多巴胺能神经元的丧失，这可以通过神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）来模拟。炎性氧化剂已成为PD和mptp相关神经退行性变的关键因素。在这里，我们发现髓过氧化物酶（MPO）是炎症过程中关键的氧化剂产生酶，在人类PD和MPTP小鼠的腹侧中脑中上调。我们还发现MPO缺失突变小鼠的腹侧中脑多巴胺能神经元比野生型小鼠更能抵抗mptp诱导的细胞毒性。MPO特异性生物标志物3-氯酪氨酸和次氯酸修饰蛋白在mptp注射小鼠的大脑中增加，支持MPO在PD模型中的氧化损伤作用。本研究表明MPO参与了MPTP的神经毒性过程，并提示MPO抑制剂可能对帕金森病有保护作用。
Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.