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

Abstract

Edited by Paul E. FraserTau 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 2 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), were based 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, and chronic traumatic encephalopathy, 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 different Tau variants to various forms of dementia. We also address the question of 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.

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

“…Cryo-EM studies on a-synuclein (Li et al, 2018a) and tau (Fitzpatrick et al, 2017;Lippens and Gigant, 2019) support their polymorphic nature, in line with the neuropathological heterogeneity reported in patients. The next challenge in this field is to relate these findings with the complex structures found in cells, and, most importantly, in the human brain.…”

The Mechanism of Tubulin Assembly into Microtubules: Insights from Structural Studies

“…Because many Tau residues remain NMR visible even in the presence of tubulin complexes, a model for the enhancement of microtubule assembly by this protein could be proposed from the NMR characterization of such Tau-tubulin complexes ( Gigant et al., 2014 ). Recent near-atomic cryo-EM data on Tau-decorated microtubules ( Kellogg et al., 2018 ) allowed discussion of the validity of the NMR-based model ( Lippens and Gigant, 2019 ).…”

Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

“…(Guo et al, 2016;Sanders et al, 2014). Recent cryo-EM structures of tau fibrils derived from brains of AD patients (Fitzpatrick et al, 2017) and other tauopathies have demonstrated unexpected insights into fibril structures and confirm that synthetic tau fibrils assume a vastly different folded structure as compared to AD brain-derived tau fibrils (for review, see Lippens and Gigant [2019]).…”