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Interaction of Amyotrophic Lateral Sclerosis (ALS)-related Mutant Copper-Zinc Superoxide Dismutase with the Dynein-Dynactin Complex Contributes to Inclusion Formation*S⃞

机译:肌萎缩性侧索硬化症(ALS)相关突变体的相互作用 铜锌超氧化物歧化酶与Dynein-Dynactin复合体的贡献。 纳入 编队*S⃞

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摘要

An important consequence of protein misfolding related to neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), is the formation of proteinaceous inclusions or aggregates within the central nervous system. We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interact and co-localize with the dynein-dynactin complex in cultured cells and affected tissues of ALS mice. In this study, we report that the interaction between mutant SOD1 and the dynein motor plays a critical role in the formation of large inclusions containing mutant SOD1. Disruption of the motor by overexpression of the p50 subunit of dynactin in neuronal and non-neuronal cell cultures abolished the association between aggregation-prone SOD1 mutants and the dynein-dynactin complex. The p50 overexpression also prevented mutant SOD1 inclusion formation and improved the survival of cells expressing A4V SOD1. Furthermore, we observed that two ALS-linked SOD1 mutants, H46R and H48Q, which showed a lower propensity to interact with the dynein motor, also produced less aggregation and fewer large inclusions. Overall, these data suggest that formation of large inclusions depends upon association of the abnormal SOD1s with the dynein motor. Whether the misfolded SOD1s directly perturb axonal transport or impair other functional properties of the dynein motor, this interaction could propagate a toxic effect that ultimately causes motor neuron death in ALS.
机译:与神经退行性疾病(包括肌萎缩性侧索硬化症(ALS))相关的蛋白质错误折叠的重要后果是在中枢神经系统内形成蛋白质包裹体或聚集体。我们以前已经表明,几个家族性的ALS连锁的铜锌超氧化物歧化酶(SOD1)突变体(A4V,G85R和G93A)与dynein-dynactin复合物相互作用并共同定位在ALS小鼠的培养细胞和受影响的组织中。在这项研究中,我们报告突变体SOD1和达因蛋白马达之间的相互作用在包含突变体SOD1的大包裹体形成中起关键作用。通过在神经元和非神经元细胞培养物中过表达动蛋白的p50亚基来破坏运动,消除了易于凝集的SOD1突变体与动力蛋白-动力蛋白复合物之间的联系。 p50的过表达还阻止了突变型SOD1包涵体的形成,并提高了表达A4V SOD1的细胞的存活率。此外,我们观察到两个ALS链接的SOD1突变体H46R和H48Q,与动力蛋白的相互作用降低,也产生了更少的聚集和更少的大包裹体。总体而言,这些数据表明,大包裹体的形成取决于异常SOD1与动力蛋白的结合。无论折叠错误的SOD1s是否直接干扰轴突运输还是削弱了动力蛋白的其他功能特性,这种相互作用都可能传播毒性作用,最终导致ALS的运动神经元死亡。

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