{
  "abstract": "Background\n\nMutations 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\n\nTo test whether PDI overexpression prevents the cellular and behavioural phenotypes induced by the ALS/FTD-associated cyclin FS621G mutation.Methods\n\nNeuro-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\n\nMutant 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\n\nPDI 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.",
  "abstract_shown": true,
  "affiliations": [
    "Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sina Shadfar",
      "orcid": "0000-0001-7626-1096"
    },
    {
      "affs": [
        0
      ],
      "name": "Sonam Parakh",
      "orcid": "0000-0002-7048-9695"
    },
    {
      "affs": [
        0
      ],
      "name": "Emma Perri"
    },
    {
      "affs": [
        0
      ],
      "name": "Cyril Jones Jagaraj"
    },
    {
      "affs": [
        0
      ],
      "name": "Sara Assar Kashani"
    },
    {
      "affs": [
        0
      ],
      "name": "Keelin Beyers"
    },
    {
      "affs": [
        0
      ],
      "name": "Audrey M G Ragagnin"
    },
    {
      "affs": [
        0
      ],
      "name": "Angela S Laird",
      "orcid": "0000-0002-6860-9192"
    },
    {
      "affs": [
        0
      ],
      "name": "Julie D Atkin",
      "orcid": "0000-0003-2427-499X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e21nmk9r6n3w0.bib",
  "cited_by": 0,
  "doi": "10.1080/13510002.2026.2732775",
  "fulltext_url": "https://europepmc.org/articles/PMC13686195",
  "id": "e21nmk9r6n3w0",
  "issns": [
    "1351-0002",
    "1743-2928"
  ],
  "landing_url": "https://europepmc.org/article/MED/42894325",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7222958636",
  "pdf_url": "https://europepmc.org/articles/PMC13686195?pdf=render",
  "pmcid": "PMC13686195",
  "pmid": "42894325",
  "published": "2026-10-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e21nmk9r6n3w0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:33Z",
      "native_id": "MED:42894325",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42894325"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Amyotrophic Lateral Sclerosis Research",
      "subfield": "neurology"
    }
  ],
  "title": "Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.",
  "title_text": "Protein disulphide isomerase protects against ALS/FTD phenotypes associated with cyclin F in zebrafish and cellular models.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:33Z",
  "url": "https://research.draconitic.com/paper/e21nmk9r6n3w0",
  "venue": "Redox report : communications in free radical research",
  "versions": []
}