Cryo-EM structures of tau filaments from Alzheimer's disease
| Autor: | Garib N. Murshudov, Anthony W. P. Fitzpatrick, Michel Goedert, Benjamin Falcon, Bernardino Ghetti, Shaoda He, Alexey G. Murzin, Sjors H.W. Scheres, Holly J. Garringer, R. Anthony Crowther |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Amyloid Cryo-electron microscopy Tau protein tau Proteins macromolecular substances Protein aggregation Protein Aggregation Pathological Article Protein filament 03 medical and health sciences 0302 clinical medicine Alzheimer Disease medicine Humans Senile plaques Amino Acid Sequence Aged Multidisciplinary biology Chemistry Cryoelectron Microscopy Brain 3. Good health Crystallography 030104 developmental biology medicine.anatomical_structure Cerebral cortex Biophysics Ultrastructure biology.protein Female 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 |
| Popis: | 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 A 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. High-resolution structures of tau filaments shed light on the ultrastructure of neurofibrillary lesions in Alzheimer’s disease. Alzheimer's disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. The lesions are made of paired helical and straight tau filaments (PHFs and SFs, respectively). Different tau filaments characterize other neurodegenerative diseases, suggesting that molecular conformers of aggregated tau underlie human tauopathies. No high-resolution structures of tau filaments are currently available. Here, Sjors Scheres and colleagues present cryo-electron microscopy (cryo-EM) maps at 3.5 A resolution and corresponding atomic models of PHFs and SFs from the brain of an individual with Alzheimer's disease. Their results show that cryo-EM enables atomic characterization of amyloid filaments from patient-derived material and could be used to study a range of neurodegenerative diseases. |
| Databáze: | OpenAIRE |
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