Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons
Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons
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DOI：
10.1016/s0002-9440(10)65396-5
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发表时间：
1999-05-01
影响因子：
6
通讯作者：
Montine, TJ
中科院分区：
文献类型：
--
作者：
Zhang, J;Perry, G;Montine, TJ
包括核酸修饰在内的氧化损伤可能导致帕金森病（PD）患者黑质（SN）多巴胺能神经变性。为了研究这些脆弱的多巴胺能神经元中核酸氧化损伤的程度和分布，我们用化学方法表征了核酸氧化的常见产物8-羟基鸟苷（8 OHG）。在PD患者中，胞质8 OHG免疫反应性在SN的神经元中是强烈的，并且在中缝背核和眼神经核的神经元中存在较小程度的免疫反应性，并且偶尔在胶质细胞中存在。与年龄匹配的对照组相比，PD患者中8 OHG免疫反应性SN神经元的比例显著更大。对多系统萎缩-帕金森型（MSA-P）和路易体痴呆（DLB）患者的中脑切片进行了检查。与对照组相比，MSA-P和DLB中SN神经元的细胞质8 OHG免疫反应性增加;然而，阳性神经元的比例显著低于PD患者。黑质内8 OHG免疫反应阳性神经元的区域分布与这三种疾病的神经变性分布相对应。在任何个体中均未观察到核8 OHG免疫反应性。负责8 OHG免疫反应性的细胞质核酸的类型进行了分析，通过预孵育从PD患者与RNA酶，DNA酶，或两种酶的中脑切片。8 OHG免疫反应性被RNase或DNase显著减弱，并被两种酶完全消除。这些结果表明，在PD患者的中脑，特别是SN中，对细胞质核酸的氧化损伤选择性增加，而在MSA-P和DLB患者中则少得多。此外，对核酸的氧化损伤主要限于细胞质，RNA和线粒体DNA都是靶点。
Oxidative damage, including modification of nucleic acids, may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson's disease (PD). To investigate the extent and distribution of nucleic acid oxidative damage in these vulnerable dopaminergic neurons, we immunohistochemically characterized a common product of nucleic acid oxidation, 8-hydroxyguanosine (8OHG). In PD patients, cytoplasmic 8OHG immunoreactivity was intense in neurons of the SN, and present to a lesser extent in neurons of the nucleus raphe dorsalis and oculomotor nucleus, and occasionally in glia. The proportion of 8OHG immunoreactive SN neurons was significantly greater in PD patients compared to age-matched controls. Midbrain sections from patients with multiple system atrophy-Parkinsonian type (MSA-P) and dementia with Lewy bodies (DLB) also were examined. These showed increased cytoplasmic 8OHG immunoreactivity in SN neurons in both MSA-P and DLB compared to controls; however, the proportion of positive neurons was significantly less than in PD patients. The regional distribution of 8OHG immunoreactive neurons within the SN corresponded to the distribution of neurodegeneration for these three diseases. Nuclear 8OHG immunoreactivity was not observed in any individual. The type of cytoplasmic nucleic acid responsible for 8OHG immunoreactivity was analyzed by preincubating midbrain sections from PD patients with RNase, DNase, or both enzymes. 8OHG immunoreactivity was substantially diminished by either RNase or DNase, and completely ablated by both enzymes. These results suggest that oxidative damage to cytoplasmic nucleic acid is selectively increased in midbrain, especially the SN, of PD patients and much less so in MSA-P and DLB patients. Moreover, oxidative damage to nucleic acid is largely restricted to cytoplasm with both RNA and mitochondrial DNA as targets.