Drosophila Tau is Required for Proper Maintenance and Survival of Neurons. Bonnie J. Bolkan, Doris Kretzschmar. CROET, L606, Oregon Hlth & Sci Univ, Portland, OR.

   Tau is a neuronal Microtubule Associated Protein (MAP) involved in both microtubule association and stabilization. Aggregation of Tau is one of the pathologies associated with Alzheimers Disease and neurodegenerative primary-tauopathies. Despite its important role in disease the molecular mechanism of Tau mediated toxicity is not well understood. Transgenic Drosophila lines have been used as a model for human Tau toxicity for over a decade. Here we address the role of the endogenous dTau by focusing on the phenotypes resulting from loss of dTau.
   While dTau expression appears to be pan-neuronal its expression is highest in the eye and photoreceptor neuron projections. This expression is required for maintenance of these neurons as the eye appears to develop normally even in GMR dTAU^RNAi flies, however within days after eclosion the eye begins to significantly degenerate. Transmission Electron Micrographs show very few intact rhabdomeres by 3 days post eclosion. Pan-neuronal knowndowns results in high levels of larval lethality and the flies that survive to adulthood show significant vaculolization in the central brain by 36 hr post eclosion but this degeneration is not progressive.
   These data support the loss of function models in human tauopathies. We, therefore, wanted to look at the effects of human (h) and bovine (b) Tau, both of which are toxic in Drosophila, on dTau. Immunohistochemistry of larval eye discs expressing bTau or hTau driven by GMR show a dramatic decrease in dTau and a change in dTau staining patterns. This decrease in dTau levels was confirmed in Westerns. Furthermore, microtubule assays show that the vast majority of hTau is phosphorylated and cytosolic yet very little dTau is still bound to microtubules. We therefore propose that the toxicity of bTau and hTau is caused by the removal of functional Tau from microtubules.