TY - JOUR
T1 - ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation
AU - Ragagnin, Audrey M.G.
AU - Sundaramoorthy, Vinod
AU - Farzana, Fabiha
AU - Gautam, Shashi
AU - Saravanabavan, Sayanthooran
AU - Takalloo, Zeinab
AU - Mehta, Prachi
AU - Do-Ha, Dzung
AU - Parakh, Sonam
AU - Shadfar, Sina
AU - Hunter, Julie
AU - Vidal, Marta
AU - Jagaraj, Cyril J.
AU - Brocardo, Mariana
AU - Konopka, Anna
AU - Yang, Shu
AU - Rayner, Stephanie L.
AU - Williams, Kelly L.
AU - Blair, Ian P.
AU - Chung, Roger S.
AU - Lee, Albert
AU - Ooi, Lezanne
AU - Atkin, Julie D.
PY - 2023/11/22
Y1 - 2023/11/22
N2 - 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 FS621G 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 FS621G 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 FS195R, 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.
AB - 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 FS621G 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 FS621G 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 FS195R, 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.
KW - Amyotrophic lateral sclerosis (ALS)
KW - Frontotemporal dementia (FTD)
KW - Pathogenic mechanisms
UR - http://www.scopus.com/inward/record.url?scp=85177436635&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/nhmrc/10305133
UR - http://purl.org/au-research/grants/nhmrc/1086887
UR - http://purl.org/au-research/grants/nhmrc/1095215
U2 - 10.1038/s41598-023-46802-9
DO - 10.1038/s41598-023-46802-9
M3 - Article
AN - SCOPUS:85177436635
SN - 2045-2322
VL - 13
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 20467
ER -