TDP-43 pathology and functional deficits in wild-type and ALS/FTD mutant cyclin F mouse models.

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 7609829 Publication Model: Print Cited Medium: Internet ISSN: 1365-2990 (Electronic) Linking ISSN: 03051846 NLM ISO Abbreviation: Neuropathol Appl Neurobiol Subsets: MEDLINE

Original Publication: Oxford, Blackwell Scientific Publications.

Amyotrophic Lateral Sclerosis*/pathology ; Frontotemporal Dementia*/pathology; Humans ; Animals ; Mice ; Infant ; Motor Neurons/pathology ; Mutation ; DNA-Binding Proteins/metabolism ; Cyclins/genetics ; Cyclins/metabolism

Aims: Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of upper and lower motor neurons leading to muscle weakness and eventually death. Frontotemporal dementia (FTD) presents clinically with significant behavioural decline. Approximately 10% of cases have a known family history, and disease-linked mutations in multiple genes have been identified in FTD and ALS. More recently, ALS and FTD-linked variants have been identified in the CCNF gene, which accounts for an estimated 0.6% to over 3% of familial ALS cases.
Methods: In this study, we developed the first mouse models expressing either wild-type (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 ^S621G throughout the murine brain by intracranial delivery of adeno-associated virus (AAV) to achieve widespread delivery via somatic brain transgenesis.
Results: These mice developed behavioural abnormalities, similar to the clinical symptoms of FTD patients, as early as 3 months of age, including hyperactivity and disinhibition, which progressively deteriorated to include memory deficits by 8 months of age. Brains of mutant CCNF_S621G mice displayed an accumulation of ubiquitinated proteins with elevated levels of phosphorylated TDP-43 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-rich (SFPQ). Furthermore, cytoplasmic TDP-43 inclusions were found in both CCNF_WT and mutant CCNF_S621G mice, recapitulating the key hallmark of FTD/ALS pathology.
Conclusions: In summary, CCNF expression in mice reproduces clinical presentations of ALS, including functional deficits and TDP-43 neuropathology with altered CCNF-mediated pathways contributing to the pathology observed.
(© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

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Keywords: TDP-43; amyotrophic lateral sclerosis; cyclin F; frontotemporal dementia; mouse models; ubiquitination

0 (DNA-Binding Proteins)
0 (Cyclins)
0 (TDP-43 protein, mouse)

Date Created: 20230323 Date Completed: 20230426 Latest Revision: 20240320

20250114

PMC10946706

10.1111/nan.12902

36951214