Abstract: Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that primarily affects the frontal and temporal lobes. Clinically, FTLD is characterized by behavioral abnormalities, language deficits, and/or movement impairments, with no approved therapeutic drugs currently available. While most cases of the FTLD cases are sporadic, several gene mutations including GRN, MAPT, TARDBP and C9ORF72 are associated with its pathogenesis. Pathologically, FTLD is classified into subtypes such as FTLD-TDP and FTLD-Tau, based on the type of protein aggregation observed in the patients’ brains. The purpose of this study is to identify potential therapeutic agents from existing drugs using patient-derived induced pluripotent cells (iPSCs). A phenotypic screening was conducted using cortical neurons differentiated from FTLD patient-derived iPSCs harboring the GRN mutation. These patient-derived neurons exhibited accelerated cell death and lysosomal enlargement compared to neurons derived from healthy donors. From a library of small compounds, three drugs were identified as effective in suppressing cell death and lysosomal enlargement: Sulfisoxazole, Telmisartan, and Ropinirole (ROPI). In this study, we highlight ROPI as an example of these candidate compounds, presenting its potential efficacy across in vitro FTLD models. Subsequent investigations examined its effects on other FTLD cases, including five familial FTLD cases such as GRN mutant iPSCs (FTLD-TDP) and MAPT mutant iPSCs (FTLD-Tau) as well as four sporadic cases. ROPI consistently suppressed neuronal cell death in all familial cases and three out of four sporadic cases, suggesting that ROPI is effective in the majority of FTLD cases. Further analysis revealed that ROPI also improves several cellular and molecular phenotypes, including lysosomal abnormalities. These findings highlight the therapeutic potential of Sulfisoxasole, Telmisartan, and ROPI as promising candidates for FTLD treatment. Further investigations into their mechanisms offer new hope for developing effective treatments for FTLD.
