MOLECULAR, GENETIC AND FUNCTIONAL SCREENING TO IDENTIFY MODIFIERS OF FTD

Cognitive decline occurs naturally with aging but is more pronounced in proteinopathies such as frontotemporal dementia. Key pathological proteins, including TDP-43, drive many of the molecular and behavioral changes observed in these disorders. Using the powerful genetic tools of Drosophila Melanogaster, we investigate these mechanisms in a spatio-temporal regulated manner. By expressing human TDP-43 in the neurons of flies, we recapitulate memory impairments as seen in patients. Behavioral testing at different time points allows us to track disease progression over time. Through immunostaining and biochemical analyses, we examine the localization and aggregation level of this protein and of its fly homolog, revealing age-dependent alterations. To connect molecular signatures with behavior, we perform single-cell transcriptomic profiling of fly brains expressing the aforementioned protein and compare these data to human datasets, identifying conserved gene expression changes. This cross-species approach enables us to pinpoint potential therapeutic targets, which we rapidly test in our model system. We evaluate known memory modulators, repurposed drugs such as anti-tumor compounds, and novel molecular pathways to identify modifiers that can alleviate disease phenotypes. Together, this work establishes a robust and versatile pre-clinical platform for dissecting neurodegenerative mechanisms.