Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis
Nonamyloid Aggregates Arising from Mature Copper/Zinc Superoxide Dismutases Resemble Those Observed in Amyotrophic Lateral Sclerosis
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DOI：
10.1074/jbc.m110.113696
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发表时间：
2010-12-31
影响因子：
4.8
通讯作者：
Meiering, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Hwang, Young-Mi;Stathopulos, Peter B.;Meiering, Elizabeth M.
蛋白质聚集是许多疾病的标志，包括肌萎缩侧索硬化症(ALS)，铜/锌超氧化物歧化酶(SOD1)的聚集参与了发病机制。我们在这里报道，在生理相关的溶液条件下，完全金属化(Holo)SOD1可以随着时间的推移经历金属化和/或二聚化的变化，并形成不具有淀粉样蛋白经典特征的聚集体。结构和染色分析证明了观察到的聚集与疾病的相关性，包括在ALS患者和小鼠模型中特异性识别聚集的抗SOD1抗体结合的新观察。肌萎缩侧索硬化症相关的SOD1突变可以促进聚集，但不是必需的。SOD1的聚集以滞后相为特征，这种滞后相被自种子或交叉种子以及非均相成核所减弱。我们根据一种扩展的聚集机制来解释这些发现，这与其他体外和体内的发现一致，这些发现指出了不同形式的SOD1形成有毒聚集体的多种途径。
Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS) where aggregation of copper/zinc superoxide dismutase (SOD1) is implicated in pathogenesis. We report here that fully metallated (holo) SOD1 under physiologically relevant solution conditions can undergo changes in metallation and/or dimerization over time and form aggregates that do not exhibit classical characteristics of amyloid. The relevance of the observed aggregation to disease is demonstrated by structural and tinctorial analyses, including the novel observation of binding of an anti-SOD1 antibody that specifically recognizes aggregates in ALS patients and mice models. ALS-associated SOD1 mutations can promote aggregation but are not essential. The SOD1 aggregation is characterized by a lag phase, which is diminished by self-or cross-seeding and by heterogeneous nucleation. We interpret these findings in terms of an expanded aggregation mechanism consistent with other in vitro and in vivo findings that point to multiple pathways for the formation of toxic aggregates by different forms of SOD1.