Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Frontotemporal Dementia (FTD) is a neurodegenerative disorder often caused by C9orf72 repeat expansions.
• Current FTD models have limitations in capturing dynamic disease processes.
• Understanding C9orf72's role in FTD pathogenesis is crucial.

Purpose of the Study:

• To investigate FTD hallmarks in undifferentiated patient-derived induced pluripotent stem cells (iPSCs).
• To explore the role of lysosome dysfunction in FTD.
• To identify novel therapeutic targets for FTD.

Main Methods:

• Utilized patient-derived iPSCs without neuronal differentiation.
• Assessed lysosomal function (pH, cathepsin activity).
• Analyzed TDP-43 proteinopathy and TFEB levels.
• Performed RNA-sequencing to identify dysregulated transcripts.
• Confirmed protein expression changes for key genes.

Main Results:

• Undifferentiated FTD iPSCs exhibit increased lysosome pH, decreased cathepsin activity, TDP-43 proteinopathy, and increased nuclear TFEB.
• Reducing lysosome pH ameliorated TDP-43 proteinopathy in FTD iPSCs.
• RNA-seq revealed dysregulated genes impacting calcium signaling, cell death, and neuronal development.
• Identified novel protein expression differences in CNTFR, Annexin A2, NANOG, and moesin.

Conclusions:

• Undifferentiated FTD iPSCs serve as a robust model for studying cellular pathology.
• Lysosome dysfunction is a critical factor in C9orf72-linked FTD.
• FTD iPSCs offer a platform for drug screening and therapeutic development.