Patient-derived Induced Pluripotent Stem Cells as a Model to Study the Biology of Frontotemporal Dementia

Frontotemporal Dementia (FTD), a group of neurodegenerative diseases commonly affecting individuals under the age of 65, can be caused by a repeat expansion (GGGGCC) in C9orf72. However, the function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD remain unclear. Diverse disease models, using human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) have identified some hallmarks associated with neurodegeneration, but these models are labor-intensive and costly. We find that undifferentiated patient-derived iPSCs, without the need for differentiation into neurons, exhibit established FTD hallmarks, including disrupted lysosome biology, 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 sequencing reveals dysregulated transcripts in FTD iPSCs, affecting calcium signaling, cell death, synaptic function, and neuronal development. Protein expression differences for some dysregulated genes, including CNTFR (neuronal survival), moesin (cytoskeletal dynamics), and NANOG (neuronal development), previously linked to neurodegenerative diseases but not FTD, were confirmed. These findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and drug screening, offering a promising approach for identifying therapeutic targets.