Patient-derived induced pluripotent stem cells with a C9orf72 expansion as a model to study frontotemporal dementia pathologies.

The neurodegenerative disorder frontotemporal dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 expansion causes FTD, however, remain unresolved. Diverse disease models, including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs), identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and postmitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including ciliary neurotrophic factor receptor (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and Moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics.