Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.
- 1Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
Abstract
Background
Mutations in CCNF, encoding cyclin F, cause a small proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Mutant cyclin F mislocalises from the nucleus to the cytoplasm, impairs the ubiquitin proteasome system, disrupts endoplasmic reticulum (ER) to Golgi transport, and triggers ER stress and apoptosis. Protein disulphide isomerase (PDI), a redox-active ER chaperone of the thioredoxin superfamily, protects against ALS phenotypes induced by mutant SOD1, TDP-43, and FUS, but its activity against mutant cyclin F has not been examined.Objectives
To test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin FS621G mutation.Methods
Neuro-2a cells were co-transfected with mCherry-tagged wild-type or mutant cyclin FS621G and V5-tagged PDI or empty vector. Subcellular localisation, XBP-1 and CHOP activation, proteasome reporter (GFPu) accumulation, nuclear morphology, and cleaved caspase-3 immunoreactivity were assessed by confocal microscopy. Transient transgenic zebrafish larvae generated by mRNA co-injection of cyclin F and PDI were assessed by photomotor response at 48 h post-fertilisation.Results
Mutant cyclin FS621G induced cytoplasmic mislocalisation, ER stress (assessed by XBP-1 and CHOP activation), proteasome dysfunction (indicated by GFPu accumulation), and apoptosis (assessed by nuclear condensation and caspase-3 activation), all of which were significantly attenuated by PDI co-expression. Zebrafish larvae expressing cyclin FS621G swam significantly shorter distances than uninjected or wildtype controls, and co-expression of PDI restored motor function to near-wildtype levels.Conclusion
PDI protects against ALS/FTD-associated mutant cyclin F in both cellular and in vivo zebrafish models, identifying PDI as a redox-based therapeutic target for CCNF-linked ALS/FTD.
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BibTeX
@article{shadfar2026protein,
title = {{Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.}},
author = {Sina Shadfar and Sonam Parakh and Emma Perri and Cyril Jones Jagaraj and Sara Assar Kashani and Keelin Beyers and Audrey M G Ragagnin and Angela S Laird and Julie D Atkin},
journal = {Redox report : communications in free radical research},
year = {2026},
month = oct,
doi = {10.1080/13510002.2026.2732775},
url = {https://europepmc.org/article/MED/42894325},
note = {CC BY},
}
RIS
TY - JOUR
TI - Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.
AU - Sina Shadfar
AU - Sonam Parakh
AU - Emma Perri
AU - Cyril Jones Jagaraj
AU - Sara Assar Kashani
AU - Keelin Beyers
AU - Audrey M G Ragagnin
AU - Angela S Laird
AU - Julie D Atkin
PY - 2026
DA - 2026/10/18
JO - Redox report : communications in free radical research
DO - 10.1080/13510002.2026.2732775
UR - https://europepmc.org/article/MED/42894325
AB - Background Mutations in CCNF, encoding cyclin F, cause a small proportion of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Mutant cyclin F mislocalises from the nucleus to the cytoplasm, impairs the ubiquitin proteasome system, disrupts endoplasmic reticulum (ER) to Golgi transport, and triggers ER stress and apoptosis. Protein disulphide isomerase (PDI), a redox-active ER chaperone of the thioredoxin superfamily, protects against ALS phenotypes induced by mutant SOD1, TDP-43, and FUS, but its activity against mutant cyclin F has not been examined.Objectives To test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin FS621G mutation.Methods Neuro-2a cells were co-transfected with mCherry-tagged wild-type or mutant cyclin FS621G and V5-tagged PDI or empty vector. Subcellular localisation, XBP-1 and CHOP activation, proteasome reporter (GFPu) accumulation, nuclear morphology, and cleaved caspase-3 immunoreactivity were assessed by confocal microscopy. Transient transgenic zebrafish larvae generated by mRNA co-injection of cyclin F and PDI were assessed by photomotor response at 48 h post-fertilisation.Results Mutant cyclin FS621G induced cytoplasmic mislocalisation, ER stress (assessed by XBP-1 and CHOP activation), proteasome dysfunction (indicated by GFPu accumulation), and apoptosis (assessed by nuclear condensation and caspase-3 activation), all of which were significantly attenuated by PDI co-expression. Zebrafish larvae expressing cyclin FS621G swam significantly shorter distances than uninjected or wildtype controls, and co-expression of PDI restored motor function to near-wildtype levels.Conclusion PDI protects against ALS/FTD-associated mutant cyclin F in both cellular and in vivo zebrafish models, identifying PDI as a redox-based therapeutic target for CCNF-linked ALS/FTD.
SN - 1351-0002
SN - 1743-2928
ER -