Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis
Mutant SOD1 inhibits ER-Golgi transport in amyotrophic lateral sclerosis
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DOI：
10.1111/jnc.12493
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发表时间：
2014-04-01
影响因子：
4.7
通讯作者：
Horne, Malcolm K.
中科院分区：
文献类型：
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作者：
Atkin, Julie D.;Farg, Manal A.;Horne, Malcolm K.
Cu/Zn-超氧化物歧化酶在家族性和散发性肌萎缩侧索硬化症中错误折叠，但尚不清楚这如何触发内质网（ER）应激或其他致病过程。在这里，我们证明突变SOD 1（mSOD 1）主要是在神经元细胞的细胞质中发现。此外，我们表明，mSOD 1抑制分泌蛋白运输从ER到高尔基体。ER-高尔基体运输与ER应激、高尔基体片段化和轴突运输有关，我们还表明，在表达mSOD 1的细胞中，ER-高尔基体运输的抑制先于ER应激、高尔基体片段化、蛋白质聚集和凋亡。恢复ER-高尔基体转运过表达的外壳体外壳蛋白II亚基Sar 1保护包涵体的形成和细胞凋亡，从而连接在ER-高尔基体转运功能障碍的细胞病理学。因此，这些发现将肌萎缩侧索硬化中的几个细胞事件联系到mSOD 1表达细胞早期发生的单一机制。
Cu/Zn-superoxide dismutase is misfolded in familial and sporadic amyotrophic lateral sclerosis, but it is not clear how this triggers endoplasmic reticulum (ER) stress or other pathogenic processes. Here, we demonstrate that mutant SOD1 (mSOD1) is predominantly found in the cytoplasm in neuronal cells. Furthermore, we show that mSOD1 inhibits secretory protein transport from the ER to Golgi apparatus. ER-Golgi transport is linked to ER stress, Golgi fragmentation and axonal transport and we also show that inhibition of ER-Golgi trafficking preceded ER stress, Golgi fragmentation, protein aggregation and apoptosis in cells expressing mSOD1. Restoration of ER-Golgi transport by over-expression of coatomer coat protein II subunit Sar1 protected against inclusion formation and apoptosis, thus linking dysfunction in ER-Golgi transport to cellular pathology. These findings thus link several cellular events in amyotrophic lateral sclerosis into a single mechanism occurring early in mSOD1 expressing cells.