Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

eLife, Journal Year: 2022, Volume and Issue: 11

Published: March 4, 2022

Abundant filamentous inclusions of tau are characteristic more than 20 neurodegenerative diseases that collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures amyloid filaments from human brain revealed distinct folds characterise many different diseases. A lack laboratory-based model systems to generate these has hampered efforts uncover the molecular mechanisms underlie Here, we report in vitro assembly conditions with recombinant replicate both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest post-translational modifications modulate filament assembly, previously observed additional densities AD CTE may arise presence inorganic salts, like phosphates sodium chloride. In into disease-relevant will facilitate studies determine their roles diseases, well development compounds specifically bind or prevent formation.

Language: Английский

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Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids

Nature, Journal Year: 2023, Volume and Issue: 621(7980), P. 701 - 710

Published: Sept. 27, 2023

Language: Английский

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Disease-specific tau filaments assemble via polymorphic intermediates

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 119 - 125

Published: Nov. 29, 2023

Abstract Intermediate species in the assembly of amyloid filaments are believed to play a central role neurodegenerative diseases and may constitute important targets for therapeutic intervention 1,2 . However, structural information about intermediate has been scarce molecular mechanisms by which amyloids assemble remain largely unknown. Here we use time-resolved cryogenic electron microscopy study vitro recombinant truncated tau (amino acid residues 297–391) into paired helical Alzheimer’s disease or chronic traumatic encephalopathy 3 We report formation shared first filament, with an ordered core comprising 302–316. Nuclear magnetic resonance indicates that same adopt rigid, β-strand-like conformations monomeric tau. At later time points, disappears observe many different filaments, structures depend on reaction conditions. end both reactions, most disappear cores as those from human brains remain. Our results provide insights processes primary secondary nucleation assembly, implications design new therapies.

Language: Английский

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Cryo-EM of prion strains from the same genotype of host identifies conformational determinants

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(11), P. e1010947 - e1010947

Published: Nov. 7, 2022

Prion strains in a given type of mammalian host are distinguished by differences clinical presentation, neuropathological lesions, survival time, and characteristics the infecting prion protein (PrP) assemblies. Near-atomic structures prions from two species with different PrP sequences have been determined but comparisons distinct same amino acid sequence needed to identify purely conformational determinants strain characteristics. Here we report 3.2 Å resolution cryogenic electron microscopy-based structure 22L purified brains mice engineered express only lacking glycophosphatidylinositol anchors [anchorless (a) 22L]. Comparison this near-atomic our recently aRML propagated inbred mouse reveals that these templates for growth via incorporation molecules sequence. Both a22L assembled as stacks forming parallel in-register intermolecular β-sheets intervening loops, single monomers spanning ordered fibril core. Each monomer shares an N-terminal steric zipper, three major arches, overall V-shape, details other features differ markedly. Thus, variations shared motifs within β-stack architecture provide structural basis differentiation genotype.

Language: Английский

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Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 1, 2024

Language: Английский

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Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(5)

Published: Jan. 28, 2025

The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 active state well studied, role reduced cysteine residues, Cys6 Cys111, SOD1 filament remains unclear. In this study, we investigated residues by determining comparing cryoelectron microscopy (cryo-EM) structures wild-type (WT) C6A/C111A under thiol-based reducing metal-depriving conditions, starting with protein samples possessing enzymatic activity. mutant more rapidly than WT protein. structure had a unique paired-protofilament arrangement, smaller core that single-protofilament observed SOD1. form developed slowly, cross-seeding experiments demonstrated predominance morphology over paired protofilaments, regardless presence Cys111 mutations. These findings highlight importance number amino acid within energy requirements for assembly. Our study provides insights into ALS pathogenesis elucidating initiation propagation formation, which potentially leads to deleterious amyloid filaments.

Language: Английский

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New Pathways Identify Novel Drug Targets for the Prevention and Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5383 - 5383

Published: March 11, 2023

Alzheimer’s disease (AD) is an incurable, progressive neurodegenerative disorder. AD a complex and multifactorial that responsible for 60–80% of dementia cases. Aging, genetic factors, epigenetic changes are the main risk factors AD. Two aggregation-prone proteins play decisive role in pathogenesis: β-amyloid (Aβ) hyperphosphorylated tau (pTau). Both them form deposits diffusible toxic aggregates brain. These biomarkers Different hypotheses have tried to explain pathogenesis served as platforms drug research. Experiments demonstrated both Aβ pTau might start processes necessary cognitive decline. The two pathologies act synergy. Inhibition formation has been old target. Recently, successful clearance by monoclonal antibodies raised new hopes treatments if detected at early stages. More recently, novel targets, e.g., improvements amyloid from brain, application small heat shock (Hsps), modulation chronic neuroinflammation different receptor ligands, microglial phagocytosis, increase myelination revealed

Language: Английский

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Structure of the nonhelical filament of the Alzheimer’s disease tau core

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(44)

Published: Oct. 25, 2023

The microtubule-associated protein tau aggregates into neurofibrillary tangles in Alzheimer’s disease (AD). main type of aggregates, the paired helical filaments (PHF), incorporate about 20% full-length rigid core. Recently, cryo-electron microscopy data showed that a protease-resistant fragment (residues 297–391) self-assembles vitro presence divalent cations to form twisted whose molecular structure resembles AD PHF [S. Lövestam et al., Elife 11 , e76494 (2022)]. To investigate whether this construct is uniquely predisposed morphology and structure, we fibrillized (297–391) under reported conditions determined its using solid-state NMR spectroscopy. Unexpectedly, assembled predominantly nontwisting ribbons core spans residues 305–357. This forms β-arch turns at 322 CGS 324 . Two protofilaments stack together via long interface stretches from G323 I354. Together, these two four-layered β-sheet sidechains are stabilized by numerous polar hydrophobic interactions. gives insight fibril morphologies conformations can be adopted different pH ionic conditions.

Language: Английский

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Alzheimer’s disease seeded tau forms paired helical filaments yet lacks seeding potential

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(9), P. 107730 - 107730

Published: Aug. 28, 2024

Language: Английский

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Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Oct. 24, 2024

Chronic wasting disease (CWD) is a widely distributed prion of cervids with implications for wildlife conservation and also human livestock health. The structures infectious prions that cause CWD other natural diseases mammalian hosts have been poorly understood. Here we report 2.8 Å resolution cryogenic electron microscopy-based structure fibrils from the brain naturally infected white-tailed deer expressing most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie fibrils, our atomic model contains single stacks molecules forming parallel in-register intermolecular β-sheets intervening loops comprising major N- C-terminal lobes within fibril cross-section. However, cervid host differ markedly rodent in many features, including ~ 180° twist relative orientation lobes. This suggests mechanisms underlying apparent transmission barrier to humans should facilitate more rational approaches development vaccines therapeutics.

Language: Английский

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