Drosophila models of human tauopathies indicate that Tau protein toxicity in vivo is mediated by soluble cytosolic phosphorylated forms of the protein

Tau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.

“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”

Tau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites.

“tau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites [19, 25–28].”

In Drosophila, tau phosphorylation at SP/TP sites decreases tau binding to microtubules, whereas replacing these sites with unphosphorylatable Ala significantly increases binding.

“In Drosophila, tau phosphorylation at proline-directed Ser and Thr (SP/TP) sites decreases tau binding to microtubules, whereas replacing these phosphorylation sites with unphosphorylatable Ala significantly increases binding [25, 26].”

Phosphorylation of tau negatively influences its ability to bind microtubules.

“Phosphorylation of tau negatively influences its ability to bind microtubules [25–27, 51, 52].”

Phosphorylation at Ser262 and Ser356 decreases tau binding to microtubules.

“Ser262 and Ser356 are located in the microtubule-binding domain, and phosphorylation at these sites decreases tau binding to microtubules [18, 19, 25, 26, 50, 51].”