ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.

Autor: Ragagnin AMG; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Sundaramoorthy V; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Farzana F; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Gautam S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Saravanabavan S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Takalloo Z; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Mehta P; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Do-Ha D; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia., Parakh S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Shadfar S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Hunter J; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Vidal M; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Jagaraj CJ; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Brocardo M; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Konopka A; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Yang S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Rayner SL; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Williams KL; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Blair IP; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Chung RS; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Lee A; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia., Ooi L; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Northfields Avenue, Wollongong, NSW, 2522, Australia., Atkin JD; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia. julie.atkin@mq.edu.au.; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC, 3086, Australia. julie.atkin@mq.edu.au.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Nov 22; Vol. 13 (1), pp. 20467. Date of Electronic Publication: 2023 Nov 22.
DOI: 10.1038/s41598-023-46802-9
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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