Cryo-EM structures of Tau filaments from Alzheimer’s disease brain
By A. Fitzpatrick, B. Falcon, Shaoda He, Alexey G. Murzin, G. Murshudov, H. J. Garringer, R. Crowther, Bernardino Ghetti, M. Goedert, Sjors H. W. Scheres. Nature, 2017
1,454 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/ea7380f85cfef9a01496af49e407ad4685619b4b
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In Molecular Biology
- J. Long
- Dennis W. Dickson
- Alexey G. Murzin
- M. Goedert
- D. Holtzman
- Sjors H. W. Scheres
- M. DeTure
- Yifan Cheng
In Physiology
Citations in the corpus
- Structures of α-Synuclein Filaments from Multiple System Atrophy (2020, background): “This finding is also reminiscent of similar results for tau filaments (4-9), even though marked differences exist between tau and α-synuclein.”
- The neuropathological diagnosis of Alzheimer’s disease (2019, positive): “5 A using cryoelectron microscopy [57].”
- Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “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”