Patient-derived Induced Pluripotent Stem Cells 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 mutation 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 post-mitotic. 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 CNTFR (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. SIGNIFICANCE STATEMENTO_LIUnderstanding the cellular pathology of Frontotemporal Dementia linked to a GGGGCC expansion in the C9orf72 gene remains a challenge. C_LIO_LIThis study shows that undifferentiated patient-derived iPSCs exhibit hallmark FTD characteristics, including lysosome dysfunction and TDP-43 proteinopathy, and identifies dysregulated genes related to neurodegeneration. C_LIO_LIThese findings highlight patient-derived iPSCs as a valuable model for studying FTD pathology and for drug screening, potentially guiding future research in therapeutic development. C_LI