| Tau is a microtubule-associated protein that is a major component of paired helical filaments, which define a class of neurodegenerative diseases termed tauopathies, including Alzheimer's disease. To further reveal tau's function in neurodegeneration, a genome-wide screen for dominant modifiers of tau-induced toxicity was conducted in a Drosophila model of tauopathy using a collection of recessively lethal P element mutagenized loss-of-function lines ("P-lethals"). Mutations in the eye color genes white and brown enhance tau toxicity, but can be suppressed by mutations in rosy. Accounting for these background effects, the completion of this screen revealed eleven suppressors and twelve enhancers. Nearly all modifiers identified did not modify polyglutamine or apoptotic degeneration. A complementary overexpression screen found at least three additional modifiers. In sum, thirty modifiers were identified, and link tau function to a diverse range of cellular processes, including lipid droplet regulation, ribosomal affinity, Golgi apparatus organization, the cell cycle and other functions in the nucleus and nucleolus. Known tau kinases shaggy/GSK-3 and par-1/MARK oppositely modify tau toxicity. Reduction of dynein suppresses toxicity, while reduction of kinesins enhances toxicity; however overexpression of milton, a kinesin-associated mitochondrial protein, suppresses toxicity. Reductions in autophagy genes enhance toxicity, indicating functional autophagy is a protective mechanism. Increased Mekk1 expression enhances tau toxicity, and Mekk1-mediated activation of p38 functions synergistically with tau to lower extracellular regulated kinase (ERK) activity. Tau phosphorylation at S202/T205 does not correlate with tau toxicity or glycogen synthase kinase 3 beta (GSK-3beta) activity, however increased toxicity correlated with increased GSK-3beta activity; GSK-3beta regulation of Armadillo/beta-catenin signaling is implicated. Finally, microRNA miR-7 and bancal, the host gene in which the miR-7 gene is embedded, both modify tau-induced toxicity and tau phosphorylation, although in opposite directions, suggesting possible negative feedback regulation between bancal and miR-7. The transcription factor yan, a target of miR-7 gene silencing, did not modify tau toxicity. These results provide novel insights into tau function and possible treatment avenues for tauopathies. |
