Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila.

Abnormally phosphorylated Tau protein, the major component of neurofibrillary tangles, is critical in the pathogenesis of Alzheimer's disease and related Tauopathies. We used Drosophila to examine the role of key disease-associated phosphorylation sites on Tau-mediated neurotoxicity. We present evidence that the late-appearing phosphorylation on Ser(238) rather than hyperphosphorylation per se is essential for Tau toxicity underlying premature mortality in adult flies. This site is also occupied at the time of neurodegeneration onset in a mouse Tauopathy model and in damaged brain areas of confirmed Tauopathy patients, suggesting a similar critical role on Tau toxicity in humans. In contrast, occupation of Ser(262) is necessary for Tau-dependent learning deficits in adult Drosophila. Significantly, occupation of Ser(262) precedes and is required for Ser(238) phosphorylation, and these temporally distinct phosphorylations likely reflect conformational changes. Because sequential occupation of Ser(262) and Ser(238) is required for the progression from Tau-mediated learning deficits to premature mortality in Drosophila, they may also play similar roles in the escalating symptom severity in Tauopathy patients, congruent with their presence in damaged regions of their brains.