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Frontotemporal dementia (FTD) presents clinically with significant behavioural decline. Approximately 10% of cases have a known family history, and disease\u2010linked mutations in multiple genes have been identified in FTD and ALS. More recently, ALS and FTD\u2010linked variants have been identified in the <jats:italic>CCNF<\/jats:italic> gene, which accounts for an estimated 0.6% to over 3% of familial ALS cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we developed the first mouse models expressing either wild\u2010type (WT) human CCNF or its mutant pathogenic variant S621G to recapitulate key clinical and neuropathological features of ALS and FTD linked to CCNF disease variants. We expressed human CCNF WT or CCNF<jats:sup>S621G<\/jats:sup> throughout the murine brain by intracranial delivery of adeno\u2010associated virus (AAV) to achieve widespread delivery via somatic brain transgenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>These mice developed behavioural abnormalities, similar to the clinical symptoms of FTD patients, as early as 3\u00a0months of age, including hyperactivity and disinhibition, which progressively deteriorated to include memory deficits by 8\u00a0months of age. Brains of mutant CCNF_S621G mice displayed an accumulation of ubiquitinated proteins with elevated levels of phosphorylated TDP\u201043 present in both CCNF_WT and mutant CCNF_S621G mice. We also investigated the effects of CCNF expression on interaction targets of CCNF and found elevated levels of insoluble splicing factor proline and glutamine\u2010rich (SFPQ). Furthermore, cytoplasmic TDP\u201043 inclusions were found in both CCNF_WT and mutant CCNF_S621G mice, recapitulating the key hallmark of FTD\/ALS pathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In summary, CCNF expression in mice reproduces clinical presentations of ALS, including functional deficits and TDP\u201043 neuropathology with altered CCNF\u2010mediated pathways contributing to the pathology observed.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12902","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T10:27:26Z","timestamp":1679567246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TDP\u201043 pathology and functional deficits in wild\u2010type and ALS\/FTD mutant cyclin F mouse models"],"prefix":"10.1111","volume":"49","author":[{"given":"Annika","family":"van Hummel","sequence":"first","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miheer","family":"Sabale","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Przybyla","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"van der Hoven","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Chan","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid F.","family":"Feiten","sequence":"additional","affiliation":[{"name":"Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine Ludwig\u2010Maximilians\u2010Universit\u00e4t M\u00fcnchen  Munich 81377 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.","family":"Chung","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars M.","family":"Ittner","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1423-0451","authenticated-orcid":false,"given":"Yazi D.","family":"Ke","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales 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