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.

肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是致命的神经退行性疾病，与遗传和病理相关。编码泛素样蛋白 ubiquilin2 的UBQLN2基因突变与家族性 ALS/FTD 相关，但其病理生理机制仍不清楚。在这里，我们证明 ALS/FTD UBQLN2 突变体 P497H 和 P506T 抑制神经元细胞中从内质网 (ER) 到高尔基体的蛋白质转运。此外，我们观察到 Sec31 阳性 ER 出口位点聚集在 UBQLN2 ^T487I患者脊髓组织中。内质网-高尔基中间体（ERGIC）和高尔基体都变得混乱和支离破碎。这会激活内质网应激并抑制内质网相关的降解。因此，本研究强调分泌蛋白运输和 ER 稳态的扰动是与 ALS/FTD 相关形式的 UBQLN2 相关的致病机制。