Cryo-EM structures of tau filaments from Alzheimer's disease
Anthony W P Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G Murzin, Garib Murshudov, Holly J Garringer, R Anthony Crowther, Bernardino Ghetti, Michel Goedert, Sjors H W Scheres, Anthony W P Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G Murzin, Garib Murshudov, Holly J Garringer, R Anthony Crowther, Bernardino Ghetti, Michel Goedert, Sjors H W Scheres
Abstract
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, 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 paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments 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 for investigation of a range of neurodegenerative diseases.
Conflict of interest statement
The authors declare no competing financial interests.
Figures
References
- Wilcock GK, Esiri MM. Plaques, tangles and dementia. A quantitative study. J Neurol Sci. 1982;56:343–356.
- Ghetti B, et al. Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol. 2015;41:24–46.
- Kidd M. Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature. 1963;197:192–193.
- Terry RD. The fine structure of neurofibrillary tangles in Alzheimer’s disease. J Neuropathol Exp Neurol. 1963;22:629–642.
- Yagishita S, Itoh Y, Nan W, Amano N. Reappraisal of the fine structure of Alzheimer’s neurofibrillary tangles. Acta Neuropathol. 1981;54:239–246.
- Crowther RA. Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci U S A. 1991;88:2288–2292.
- Wischik CM, et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988;85:4884–4888.
- Braak H, Del Tredici K. Potential pathways of abnormal Tau and α-synuclein dissemination in sporadic Alzheimer’s and Parkinson’s diseases. Cold Spring Harb Perspect Biol. 2016;8:a023630.
- Jackson SJ, et al. Short fibrils constitute the major species of seed-competent Tau in the brains of mice transgenic for human P301S Tau. J Neurosci. 2016;36:762–772.
- Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–526.
- Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration. Brain. 2017;140:266–278.
- Crowther RA, Goedert M. Abnormal tau-containing filaments in neurodegenerative diseases. J Struct Biol. 2000;130:271–279.
- Guo JL, et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J Exp Med. 2016;213:2635–2654.
- Schmidt M, et al. Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM. Proc Natl Acad Sci U S A. 2015;112:11858–11863.
- Colvin MT, et al. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J Am Chem Soc. 2016;138:9663–9674.
- Lu JX, et al. Molecular structure of β-amyloid fibrils in Alzheimer’s disease brain tissue. Cell. 2013;154:1257–1268.
- Wälti MA, et al. Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril. Proc Natl Acad Sci U S A. 2016;113:E4976–4984.
- Tuttle MD, et al. Solid-state NMR structure of a pathogenic fibril of full-length human α-synuclein. Nat Struct Mol Biol. 2016;23:409–415.
- Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8:159–168.
- McEwan WA, et al. Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc Natl Acad Sci U S A. 2017;114:574–579.
- He S, Scheres SHW. Helical reconstruction in RELION. J Struct Biol. 2017 doi: 10.1016/j.jsb.2017.02.003.
- Fitzpatrick AWP, et al. Atomic structure and hierarchical assembly of a cross-β amyloid fibril. Proc Natl Acad Sci U S A. 2013;110:5468–5473.
- Jakes R, Novak M, Davison M, Wischik CM. Identification of 3- and 4-repeat tau isoforms within the PHF in Alzheimer’s disease. EMBO J. 1991;10:2725–2729.
- Wischik CM, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988;85:4506–4510.
- Taniguchi-Watanabe S, et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 2016;131:267–280.
- Dan A, et al. Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain. Acta Neuropathol Commun. 2013;1:54.
- Crick FH, Rich A. Structure of polyglycine II. Nature. 1955;176:780–781.
- Jicha GA, Bowser R, Kazam IG, Davies P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res. 1997;48:128–132.
- Bibow S, et al. The dynamic structure of filamentous tau. Angew Chem Int Ed Engl. 2011;50:11520–11524.
- Carmel G, Mager EM, Binder LI, Kuret J. The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem. 1996;271:32789–32795.
- Poorkaj P, et al. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol. 2002;52:511–516.
- Hayashi S, et al. Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol. 2002;51:525–530.
- Clavaguera F, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–9540.
- Sunde M, et al. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J Mol Biol. 1997;273:729–739.
- Govaerts C, Wille H, Prusiner SB, Cohen FE. Evidence for assembly of prions with left-handed beta-helices into trimers. Proc Natl Acad Sci U S A. 2004;101:8342–8347.
- Kadavath H, et al. Folding of the Tau protein on microtubules. Angew Chem Int Ed Engl. 2015;54:10347–10351.
- Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006;75:333–366.
- von Bergen M, et al. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000;97:5129–5134.
- Xie C, et al. Identification of key amino acids responsible for the distinct aggregation properties of microtubule‐associated protein 2 and tau. J Neurochem. 2015;135:19–26.
- Sawaya MR, et al. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature. 2007;447:453–457.
- Gustke N, Trinczek B, Biernat J, Mandelkow EM, Mandelkow E. Domains of tau protein and interactions with microtubules. Biochemistry. 1994;33:9511–9522.
- Kaufman SK, et al. Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron. 2016;92:796–812.
- Kajava AV, Steven AC. Beta-rolls, beta-helices, and other beta-solenoid proteins. Adv Protein Chem. 2006;73:55–96.
- Wasmer C, et al. Amyloid fibrils of the HET-s(218-289) prion form a beta solenoid with a triangular hydrophobic core. Science. 2008;319:1523–1526.
- Riek R, Eisenberg DS. The activities of amyloids from a structural perspective. Nature. 2016;539:227–235.
- Herrmann US, et al. Structure-based drug design identifies polythiophenes as antiprion compounds. Sci Transl Med. 2015;7:299ra123.
- Åslund A, et al. Novel pentameric thiophene derivatives for in vitro and in vivo optical imaging of a plethora of protein aggregates in cerebral amyloidoses. ACS Chem Biol. 2009;4:673–684.
- Kolb HC, Andrés JI. Tau positron emission tomography imaging. Cold Spring Harb Perspect Biol. 2017;9:a023721.
- Spina S, et al. The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family. Brain. 2008;131:72–89.
- Falcon B, et al. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2015;290:1049–1065.
- Zheng SQ, et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat Methods. 2017;14:331–332.
- Zhang K. Gctf: Real-time CTF determination and correction. J Struct Biol. 2016;193:1–12.
- Chen S, et al. High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy. 2013;135:24–35.
- Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr D. 2010;66:486–501.
- Murshudov GN, Vagin AA, Dodson EJ. Refinement of Macromolecular Structures by the Maximum-Likelihood Method. Acta Crystallogr D. 1997;53:240–255.
- Iverson TM, Alber BE, Kisker C, Ferry JG, Rees DC. A closer look at the active site of gamma-class carbonic anhydrases: high-resolution crystallographic studies of the carbonic anhydrase from Methanosarcina thermophila. Biochemistry. 2000;39:9222–9231.
- Chen VB, et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D. 2010;66:12–21.
Source: PubMed