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

Audrey M. G. Ragagnin; Vinod Sundaramoorthy; Fabiha Farzana; Shashi Gautam; Sayanthooran Saravanabavan; Zeinab Takalloo; Prachi Mehta; Dzung Do-Ha; Sonam Parakh; Sina Shadfar; Julie Hunter; Marta Vidal; Cyril J. Jagaraj; Mariana Brocardo; Anna Konopka; Shu Yang; Stephanie L. Rayner; Kelly L. Williams; Ian P. Blair; Roger S. Chung; Albert Lee; Lezanne Ooi; Julie D. Atkin

doi:10.1038/s41598-023-46802-9

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

Audrey M. G. Ragagnin, Vinod Sundaramoorthy, Fabiha Farzana, Shashi Gautam, Sayanthooran Saravanabavan, Zeinab Takalloo, Prachi Mehta, Dzung Do-Ha, Sonam Parakh, Sina Shadfar, Julie Hunter, Marta Vidal, Cyril J. Jagaraj, Mariana Brocardo, Anna Konopka, Shu Yang, Stephanie L. Rayner, Kelly L. Williams, Ian P. Blair, Roger S. ChungAlbert Lee, Lezanne Ooi, Julie D. Atkin

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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	https://doi.org/10.1038/s41598-023-46802-9
Publication status	Published - 22 Nov 2023

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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.

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10.1038/s41598-023-46802-9Licence: CC BY

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Ragagnin, A. M. G., Sundaramoorthy, V., Farzana, F., Gautam, S., Saravanabavan, S., Takalloo, Z., Mehta, P., Do-Ha, D., Parakh, S., Shadfar, S., Hunter, J., Vidal, M., Jagaraj, C. J., Brocardo, M., Konopka, A., Yang, S., Rayner, S. L., Williams, K. L., Blair, I. P., ... Atkin, J. D. (2023). ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation. Scientific Reports, 13(1), 1-20. Article 20467. https://doi.org/10.1038/s41598-023-46802-9

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

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. ",

author = "Ragagnin, {Audrey M. G.} and Vinod Sundaramoorthy and Fabiha Farzana and Shashi Gautam and Sayanthooran Saravanabavan and Zeinab Takalloo and Prachi Mehta and Dzung Do-Ha and Sonam Parakh and Sina Shadfar and Julie Hunter and Marta Vidal and Jagaraj, {Cyril J.} and Mariana Brocardo and Anna Konopka and Shu Yang and Rayner, {Stephanie L.} and Williams, {Kelly L.} and Blair, {Ian P.} and Chung, {Roger S.} and Albert Lee and Lezanne Ooi and Atkin, {Julie D.}",

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.",

year = "2023",

month = nov,

day = "22",

doi = "10.1038/s41598-023-46802-9",

language = "English",

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journal = "Scientific Reports",

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Ragagnin, AMG, Sundaramoorthy, V, Farzana, F , Gautam, S , Saravanabavan, S , Takalloo, Z , Mehta, P, Do-Ha, D, Parakh, S , Shadfar, S , Hunter, J, Vidal, M, Jagaraj, CJ, Brocardo, M, Konopka, A, Yang, S , Rayner, SL , Williams, KL , Blair, IP , Chung, RS , Lee, A, Ooi, L & Atkin, JD 2023, 'ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation', Scientific Reports, vol. 13, no. 1, 20467, pp. 1-20. https://doi.org/10.1038/s41598-023-46802-9

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.

N1 - 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.

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 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.

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 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.

UR - https://purl.org/au-research/grants/nhmrc/1086887

UR - https://purl.org/au-research/grants/nhmrc/1095215

UR - http://www.scopus.com/inward/record.url?scp=85177436635&partnerID=8YFLogxK

U2 - 10.1038/s41598-023-46802-9

DO - 10.1038/s41598-023-46802-9

M3 - Article

C2 - 37993492

SN - 2045-2322

VL - 13

SP - 1

EP - 20

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 20467

ER -

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

Abstract

Bibliographical note

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Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

Disruption to intracellular trafficking as a central pathogenic mechanism in amyotrophic lateral sclerosis

Cite this

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Projects

Developing insight into the molecular origins of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis

Disruption to intracellular trafficking as a central pathogenic mechanism in amyotrophic lateral sclerosis

Cite this