Adult-onset tau expression in Drosophila: investigating isoform toxicity, sex differences and genetic modifiers

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal accumulation of the tau protein, leading to progressive neuronal dysfunction and cell death. Although tau has been extensively studied, the specific contributions of different tau isoforms and the influence of biological sex on disease progression remain poorly understood. This thesis used an adult-onset, pan-neuronal expression system in fruit flies (Drosophila melanogaster) to systematically examine how various human tau isoforms affect behaviour, lifespan, and brain health. Initial analyses of all six tau isoforms revealed distinct, isoform- and sex-specific disruptions in locomotion and sleep. Notably, the 1N4R-TauWT isoform caused pronounced impairments in movement, with female flies generally more affected than males. Follow-up dose–response experiments with a highly pathogenic phospho-mimetic tau variant, 0N4R-TauE14, uncovered marked sexual dimorphism: increased expression reduced activity and increased daytime sleep in females, while it triggered hyperactivity and sleep loss in males. Overexpression of 0N4R-TauWT and 0N4R-TauE14 significantly shortened lifespan and induced widespread brain vacuolization consistent with neurodegeneration - again with females showing greater vulnerability. These behavioural and histological phenotypes consistently correlated with tau burden. To investigate the molecular drivers of these effects, a targeted genetic screen identified several genes that modulate tau-induced sleep abnormalities, implicating pathways related to neural signalling, protein homeostasis, and immune function. Together, these findings highlight the complex interactions between tau isoform, expression level, and biological sex in shaping disease outcomes, and point to novel genetic modifiers that could inform future therapeutic strategies for tauopathies.