Tau is an axonal microtubule-associated protein. Tau interaction with microtubules is regulated by phosphorylation. Hyperphosphorylation of tau is implicated in microtubule destabilization related to neurodegenerative disorders. However, how tau phosphorylation leads to microtubule destabilization is unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration can be explained by the disassembly and impaired functionality of the tau envelopes.

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Institut Curie Université PSL CNRS UMR3348 Orsay France

Institute of Biotechnology Czech Academy of Sciences BIOCEV Vestec Czech Republic

Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Université Paris Saclay CNRS UMR3348 Orsay France

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