Tau isoform-specific effects on lifespan in a Drosophila melanogaster model of glial tauopathy

Abstract

Tauopathies are a class of neurodegenerative diseases characterized by the abnormal phosphorylation and accumulation of the protein, tau. This abnormal accumulation occurs in both neuronal and glial cells and correlates with loss of normal functioning and cell death. In the human brain, tau has six main alternatively spliced isoforms (0N3R, 0N4R, 1N3R, 1N4R, 2N3R and 2N4R) that differ in the inclusion of one or two N-terminal inserts (N) and the second of four microtubule-binding domain repeat regions (R). 4R tau has been shown to aggregate more readily and exhibit greater toxicity than 3R tau in neurons, but isoform-specific effects on glial cells have yet to be elucidated. In this study, we utilized a fruit fly, Drosophila melanogaster, model of glial tauopathy to determine tau isoform-specific effects on toxicity. 0N3R and 0N4R were overexpressed in Drosophila glia and lifespan was measured as an indicator of toxicity. We found an interaction of the isoform type - 0N3R and 0N4R - with tau toxicity. Glial tau overexpression of both isoforms reduced lifespan in comparison to control, with 0N4R tau isoform resulting in a greater decrease in fly lifespan than 0N3R tau isoform. Generally, these results suggest that isoform type has an effect on tau toxicity when expressed in Drosophila glial cells.