Elucidating Tau function and dysfunction in the era of cryo-EM

International audienceTau is a microtubule-associated protein involved in the regulation of axonal microtubules in neurons. In pathological conditions, it forms fibrils that are molecular hallmarks of neurological disorders known as Tauopathies. In the last two years, cryo-EM has given unprecedented high-resolution views of Tau in both physiological and pathological conditions. We review here these new findings and put them into the context of the knowledge about Tau before this structural breakthrough. The first structures of Tau fibrils, a molecular hallmark of Alzheimer’s disease (AD), werebased on fibrils from the brain of an individual with AD and, along with similar patient-derived structures, have set the gold standard for the field. Cryo-EM structures of Tau fibers in three distinct diseases, AD, Pick’s disease (PiD) and Chronic Traumatic Encephalopathy (CTE), represent the end-points of Tau’s molecular trajectory. We propose that the recent Tau structures may call for a re-examination of databases that link differentTau variants to various forms of dementia. We also address the question how this structural information may link Tau’s functional and pathological aspects. Because this structural information on Tau was obtained in a very short period, the new structures should be viewed in light of earlier structural observations and past and present functional data to shed additional light on Tau function and dysfunction