Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases
Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases
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DOI：
10.1074/jbc.m414327200
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发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Li, L
中科院分区：
文献类型：
--
作者：
Choi, J;Rees, HD;Li, L
尽管氧化应激与阿尔茨海默病（AD）和帕金森病（PD）的发病机制密切相关，但氧化损伤的特定蛋白质靶标的身份仍然很大程度上未知。在此，我们报道铜锌超氧化物歧化酶 (SOD1) 是一种关键的抗氧化酶，其突变与常染色体显性神经退行性疾病家族性肌萎缩侧索硬化症 (ALS) 有关，是 AD 和 PD 大脑氧化损伤的主要目标。通过结合二维凝胶电泳、免疫印迹分析和质谱分析，我们鉴定了四种人脑 SOD1 亚型，其 pI 值分别为 6.3、6.0、5.7 和 5.0。其中，SOD1 pI 6.0亚型通过羰基化被氧化修饰，并且pI 5.0亚型在AD和PD中选择性积累。此外，Cys-146（SOD1 的一个半胱氨酸残基，在家族性 ALS 中发生突变）在 AD 和 PD 大脑中被氧化为半胱氨酸。定量蛋白质印迹分析表明，AD 和 PD 中 SOD1 同工型的总水平显着增加。此外，免疫组织化学和双荧光标记研究表明，SOD1 形成蛋白质聚集体，与 AD 大脑中的淀粉样老年斑和神经原纤维缠结相关。这些发现首次表明 SOD1 氧化损伤参与散发性 AD 和 PD 的发病机制。这项工作表明 AD、PD 和 ALS 可能具有共同或重叠的致病机制，类似的治疗策略可能针对这些机制。
Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease ( AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu, Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of two-dimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.