Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress
Amyotrophic lateral sclerosis-linked UBQLN2 mutants inhibit endoplasmic reticulum to Golgi transport, leading to Golgi fragmentation and ER stress
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DOI：
10.1007/s00018-019-03394-w
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发表时间：
2019-12-04
影响因子：
8
通讯作者：
Atkin, Julie D.
中科院分区：
文献类型：
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作者：
Halloran, Mark;Ragagnin, Audrey M. G.;Atkin, Julie D.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是两种在遗传和病理上相关的致死性神经退行性疾病。编码泛素样蛋白ubiquilin 2的UBQLN 2基因突变与家族性ALS/FTD相关，但其病理生理机制尚不清楚。在此，我们证明ALS/FTD UBQLN 2突变体P497 H和P506 T抑制神经元细胞中蛋白质从内质网（ER）转运至高尔基体。此外，我们观察到Sec 31阳性ER出口位点聚集在UBQLN 2（T487 I）患者脊髓组织中。内质网-高尔基体中间（ERGIC）区室和高尔基体都变得混乱和碎片化。这激活ER应激并抑制ER相关降解。因此，这项研究强调了分泌蛋白运输和ER稳态的扰动作为与ALS/FTD相关形式的UBQLN 2相关的致病机制。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that are related genetically and pathologically. Mutations in the UBQLN2 gene, encoding the ubiquitin-like protein ubiquilin2, are associated with familial ALS/FTD, but the pathophysiological mechanisms remain unclear. Here, we demonstrate that ALS/FTD UBQLN2 mutants P497H and P506T inhibit protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus in neuronal cells. In addition, we observed that Sec31-positive ER exit sites are clustered in UBQLN2(T487I) patient spinal cord tissues. Both the ER-Golgi intermediate (ERGIC) compartment and the Golgi become disorganised and fragmented. This activates ER stress and inhibits ER-associated degradation. Hence, this study highlights perturbations in secretory protein trafficking and ER homeostasis as pathogenic mechanisms associated with ALS/FTD-associated forms of UBQLN2.