Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
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DOI：
10.1093/hmg/ddw180
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发表时间：
2016-08-01
影响因子：
3.5
通讯作者：
Yoshii, Fumihito
中科院分区：
文献类型：
--
作者：
Hadano, Shinji;Mitsui, Shun;Yoshii, Fumihito
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是大脑和脊髓中运动神经元的选择性丧失。 ALS 的发病机制涉及多种毒性途径，例如氧化应激、错误折叠蛋白积累和功能失调的自噬。然而，体内多种因素之间相互作用的分子基础仍不清楚。在这里，我们报告了两个独立的 ALS 连锁自噬相关基因产物； SQSTM1/p62和ALS2/alsin，但不是抗氧化相关因子； NFE2L2/Nrf2 与突变 SOD1 转基因 ALS 模型的发病机制有关。我们在 Nfe2l2-null、Sqstm1-null 或 Sqstm1/Als2-double null 背景上生成了 SOD1H46R 小鼠。 SQSTM1 的缺失而非 NFE2L2 的缺失会加剧疾病症状。 SQSTM1 和 ALS2 同时失活进一步加速了疾病的发作。生化分析显示，SQSTM1 的缺失在疾病中期增加了不溶性 SOD1 的水平，而在疾病末期则没有进一步升高。值得注意的是，SQSTM1 的缺失会抑制突变型 SOD1 依赖性不溶性多泛素化蛋白的积累，而 ALS2 的缺失则会增强这种积累。组织病理学检查表明，SQSTM1 的缺失会加速运动神经元变性，并伴随泛素阳性聚集物在脊髓神经元中的优先积累。由于 SQSTM1 缺失对 SOD1H46R 小鼠的危害比缺乏 ALS2 更有害，因此此类聚集物在神经元中的选择性积累可能比生化可检测的不溶性蛋白质更具侮辱性。总的来说，两个 ALS 相关因子 SQSTM1 和 ALS2 通过可能通过自噬-内溶酶体系统调节神经元蛋白质稳态，对突变型 SOD1 介导的毒性具有独特但附加的保护作用。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transgenic ALS models. We generated SOD1H46R mice either on a Nfe2l2-null, Sqstm1-null, or Sqstm1/Als2-double null background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Biochemical analyses revealed that loss of SQSTM1 increased the level of insoluble SOD1 at the intermediate stage of the disease, whereas no further elevation occurred at the end-stage. Notably, absence of SQSTM1 rather suppressed the mutant SOD1-dependent accumulation of insoluble polyubiquitinated proteins, while ALS2 loss enhanced it. Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Since SQSTM1 loss is more detrimental to SOD1H46R mice than lack of ALS2, the selective accumulation of such aggregates in neurons might be more insulting than the biochemically-detectable insoluble proteins. Collectively, two ALS-linked factors, SQSTM1 and ALS2, have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating neuronal proteostasis possibly through the autophagy-endolysosomal system.