IDENTIFYING GENETIC MODIFIERS OF TAU-INDUCED INACTIVITY IN A <EM>DROSOPHILA</EM> MODEL OF ADULT-ONSET NEURODEGENERATION

Tauopathies, such as Alzheimer’s disease, are neurodegenerative disorders characterised by abnormal accumulation of hyperphosphorylated tau protein. While tau pathology is strongly associated with neuronal dysfunction and degeneration, the mechanisms by which tau exerts its toxic effects remain poorly understood. Changes in behaviour often occur early in tauopathies, before widespread neurodegeneration. One such change is increased behavioural inactivity, which can reflect impaired neurophysiology. To investigate the genetic basis of tau-induced inactivity, an inducible, pan-neuronal tauopathy model in Drosophila melanogaster was used. This model allows rapid genetic manipulation and large-scale, systematic screening. We observe that adult-onset tau overexpression reduces lifespan, induces neurodegeneration, and causes a sexually dimorphic activity phenotype, with females exhibiting increased periods of inactivity during the day and males exhibiting decreased periods of inactivity during the day. An initial genome-wide chromosomal deficiency screen, covering ~98% of the fly genome, identified genetic modifiers that altered tau-induced inactivity. The current study builds on this work and aims to narrow large rescuing chromosomal deficiencies to individual genes that modify this phenotype. This is achieved using quantitative behavioural analysis, overlapping deficiency mapping, RNAi and molecular analysis of tau pathology. Refining the initial genome screen allows assessment of how genetic variation influences tau-induced neurodegeneration and behavioural inactivity. Ongoing behavioural analysis using the Drosophila Activity Monitor (DAM) system, together with molecular analysis, is identifying candidate genes and pathways that modify tau-induced inactivity and neurodegeneration. This work provides insight into genetic pathways regulating tau toxicity and may be relevant to therapeutic approaches for tauopathies.