Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia.
Sci Rep. 2023 Nov 22;13(1):20467. doi: 10.1038/s41598-023-46802-9.
Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin F inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin F also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin F, and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.
肌萎缩性侧索硬化症（ALS）是一种严重的神经退行性疾病，属于额颞叶痴呆（FTD）疾病谱的一部分。编码细胞周期蛋白 F 的 CCNF 基因突变存在于散发性和家族性 ALS 和 FTD 中。然而，神经退行性变的病理生理机制仍不清楚。内质网（ER）和高尔基体区室的正常功能对于正常的生理活动和维持细胞活力至关重要。在这里，我们证明 ALS/FTD 相关变异细胞周期蛋白 F 通过内质网出口部位 COPII 小泡失调的机制抑制 ER 到高尔基体的分泌蛋白运输。与这一发现一致的是，细胞周期蛋白 F 还诱导高尔基体的片段化并激活内质网应激、内质网相关降解和细胞凋亡。用第二种 ALS/FTD 变异细胞周期蛋白 F 和皮质原代神经元证实了高尔基体片段化和内质网应激的诱导。因此，这项研究为涉及到分泌蛋白运输和 ER-Golgi 平衡紊乱的 ALS/FTD 变异细胞周期蛋白 F 相关致病机制提供了新的见解。
