Projects per year
Abstract
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 S621G 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 S621G 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 S195R, 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.
Original language | English |
---|---|
Article number | 20467 |
Pages (from-to) | 1-20 |
Number of pages | 20 |
Journal | Scientific Reports |
Volume | 13 |
Issue number | 1 |
DOIs | |
Publication status | Published - 22 Nov 2023 |
Bibliographical note
Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.Fingerprint
Dive into the research topics of 'ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation'. Together they form a unique fingerprint.Projects
- 2 Active
-
Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis
Blair, I., Atkin, J., Chung, R., Guillemin, G., Ooi, L., Denis, B., Molloy, M., Yerbury, J., Cole, N., Karl, T. & Wilson, W.
1/01/16 → …
Project: Research
-
Disruption to intracellular trafficking as a central pathogenic mechanism in amyotrophic lateral sclerosis
Atkin, J., Cole, N., Chung, R., Rizos, H. & Bell, T.
1/01/15 → …
Project: Research