Abstract
Tau 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.
Highlights
Tau is a microtubule-associated protein involved in the regulation of axonal microtubules in neurons
Polymorphic structures of both amyloid- [9] and ␣-synuclein fibrils [10, 11] were solved. Whereas all of these accomplishments have given tremendous insight into the molecular functioning of the brain, the samples that were used were invariably made from overexpressed proteins, except for one: The first structures of Tau fibrils, the other molecular hallmark of Alzheimer’s disease (AD), were based on carefully selected fibrils from the brain of a deceased patient [12]. This incredible tour de force of “structural biology on a patient”—and the subsequent structures of Tau fibrils isolated from the brain of patients suffering from Pick’s disease (PiD) [13] or from chronic traumatic encephalopathy (CTE) [14]– have clearly set a gold standard for the field
The turn region observed in AD paired helical filaments (PHFs) is not visible in the heparin-induced fibrils, but at least in the synthetic fibers obtained with 4R-Tau, the chain does turn on itself around a peptide centered in the R2 repeat (Lys290–Pro301) [17]
Summary
Tau is a microtubule-associated protein involved in the regulation of axonal microtubules in neurons. In its three-dimensional structure (PDB code 6EHV), this fragment adopts a turn comparable with the one found in the AD-Tau fibrils (Fig. 3), underscoring its character of “folded protein.” this same (DFKDRV) peptide was found to enhance the affinity for the MT surface of a Tau fragment spanning the first three repeats by a factor of 2.5 [20], so it remains an open question what conformation this peptide adopts in the physiological conformation of Tau and notably at the microtubule surface (see below).
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