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      Cryo-EM structures of Tau filaments from Alzheimer’s disease brain

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          Abstract

          Alzheimer’s disease (AD) is the most common neurodegenerative disease, and there are no mechanism-based therapies. AD is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in cerebral cortex. Neurofibrillary lesions are made of paired helical and straight Tau filaments (PHFs and SFs), whereas Tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of Tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4–3.5 Å resolution and corresponding atomic models of PHFs and SFs from AD brain. Filament cores are made of two identical protofilaments comprising residues 306–378 of Tau, which adopt a combined cross-β/β-helix structure and define the seed for Tau aggregation. PHFs and SFs differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way to study a range of neurodegenerative diseases.

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          Most cited references35

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          Common core structure of amyloid fibrils by synchrotron X-ray diffraction.

          Tissue deposition of normally soluble proteins as insoluble amyloid fibrils is associated with serious diseases including the systemic amyloidoses, maturity onset diabetes, Alzheimer's disease and transmissible spongiform encephalopathy. Although the precursor proteins in different diseases do not share sequence homology or related native structure, the morphology and properties of all amyloid fibrils are remarkably similar. Using intense synchrotron sources we observed that six different ex vivo amyloid fibrils and two synthetic fibril preparations all gave similar high-resolution X-ray fibre diffraction patterns, consistent with a helical array of beta-sheets parallel to the fibre long axis, with the strands perpendicular to this axis. This confirms that amyloid fibrils comprise a structural superfamily and share a common protofilament substructure, irrespective of the nature of their precursor proteins. Copyright 1997 Academic Press Limited.
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            Is Open Access

            Helical reconstruction in RELION

            We describe a new implementation for the reconstruction of helical assemblies in the empirical Bayesian framework of RELION. Our approach calculates optimal linear filters for the 3D reconstruction by embedding helical symmetry operators in Fourier-space, and deals with deviations from perfect helical symmetry through Gaussian-shaped priors on the orientations of individual segments. By incorporating our approach into the standard pipeline for single-particle analysis in RELION, our implementation aims to be easily accessible for non-experienced users. Although our implementation does not solve the problem that grossly incorrect structures can be obtained when the wrong helical symmetry is imposed, we show for four different test cases that it is capable of reconstructing structures to near-atomic resolution.
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              Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure.

              We have searched for a minimal interaction motif in tau protein that supports the aggregation into Alzheimer-like paired helical filaments. Digestion of the repeat domain with different proteases yields a GluC-induced fragment comprising 43 residues (termed PHF43), which represents the third repeat of tau plus some flanking residues. This fragment self assembles readily into thin filaments without a paired helical appearance, but these filaments are highly competent to nucleate bona fide PHFs from full-length tau. Probing the interactions of PHF43 with overlapping peptides derived from the full tau sequence yields a minimal hexapeptide interaction motif of (306)VQIVYK(311) at the beginning of the third internal repeat. This motif coincides with the highest predicted beta-structure potential in tau. CD and Fourier transform infrared spectroscopy shows that PHF43 acquires pronounced beta structure in conditions of self assembly. Point mutations in the hexapeptide region by proline-scanning mutagenesis prevent the aggregation. The data indicate that PHF assembly is initiated by a short fragment containing the minimal interaction motif forming a local beta structure embedded in a largely random-coil protein.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                8 July 2017
                05 July 2017
                13 July 2017
                05 January 2018
                : 547
                : 7662
                : 185-190
                Affiliations
                [1 ]MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
                [2 ]Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
                Author notes
                Article
                NIHMS882516
                10.1038/nature23002
                5552202
                28678775
                8d2418ef-fcc8-437c-bba8-e00643f3e8b3

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