Abstract
AbstractPost‐translational modifications of Tau are emerging as key players in determining the onset and progression of different tauopathies such as Alzheimer's disease, and are recognized to mediate the structural diversity of the disease‐specific Tau amyloids. Here we show that the E3 ligase CHIP catalyzes the site‐specific ubiquitination of Tau filaments both in vitro and in cellular models, proving that also Tau amyloid aggregates are direct substrate of PTMs. Transmission electron microscopy and mass spectrometry analysis on ubiquitin‐modified Tau amyloids revealed that the conformation of the filaments restricts CHIP‐mediated ubiquitination to specific positions of the repeat domain, while only minor alterations in the structure of the fibril core were inferred using seeding experiments in vitro and in a cell‐based tauopathy model. Overexpression of CHIP significantly increased the ubiquitination of exogenous PHF, proving that the ligase can interact and modify Tau aggregates also in a complex cellular environment.
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