Cryo-EM structures of amyloid-β 42 filaments from human brains

Science, Journal Year: 2022, Volume and Issue: 375(6577), P. 167 - 172

Published: Jan. 14, 2022

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss memory and other cognitive functions the filamentous assembly Aβ tau in brain. The peptides into that end at residue 42 central event. Yang et al . used electron cryo–electron microscopy to determine structures from brain (see Perspective Willem Fändrich). They identified two types related S-shaped filaments, each consisting identical protofilaments. These will inform development better vitro animal models, inhibitors assembly, imaging agents with increased specificity sensitivity. —SMH

Language: Английский

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Structures of α-synuclein filaments from human brains with Lewy pathology

Nature, Journal Year: 2022, Volume and Issue: 610(7933), P. 791 - 795

Published: Sept. 15, 2022

Language: Английский

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The expanding amyloid family: Structure, stability, function, and pathogenesis

Cell, Journal Year: 2021, Volume and Issue: 184(19), P. 4857 - 4873

Published: Sept. 1, 2021

Language: Английский

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The molecular basis for cellular function of intrinsically disordered protein regions

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

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Structure of pathological TDP-43 filaments from ALS with FTLD

Nature, Journal Year: 2021, Volume and Issue: 601(7891), P. 139 - 143

Published: Dec. 8, 2021

Language: Английский

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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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Tauopathies: new perspectives and challenges

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: April 7, 2022

Abstract Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with range phenotypes that include cognitive/behavioral-disorders, movement disorders, language and non-specific amnestic symptoms in advanced age. Pathologically, be classified based on the predominant tau isoforms inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) blood-based biomarkers have potential to used as routine diagnostic strategy evaluation patients tauopathies. As strongly linked neuropathologically genetically protein abnormalities, there is growing interest pursuing tau-directed therapeutics for disorders. Here we synthesize emerging lessons from clinical, pathological, genetic, experimental studies toward unified concept these may accelerate therapeutics. Conclusions Since still untreatable diseases, efforts been made depict clinical pathological characteristics, identify biomarkers, elucidate underlying pathogenesis achieve early diagnosis develop disease-modifying therapies.

Language: Английский

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Age-dependent formation of TMEM106B amyloid filaments in human brains

Nature, Journal Year: 2022, Volume and Issue: 605(7909), P. 310 - 314

Published: March 28, 2022

Abstract Many age-dependent neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by abundant inclusions of amyloid filaments. Filamentous the proteins tau, amyloid-β, α-synuclein transactive response DNA-binding protein (TARDBP; also known TDP-43) most common 1,2 . Here we used structure determination cryogenic electron microscopy to show that residues 120–254 lysosomal type II transmembrane 106B (TMEM106B) form filaments in human brains. We determined structures TMEM106B from a number brain regions 22 individuals with deposits, including those resulting sporadic inherited tauopathies, amyloid-β amyloidoses, synucleinopathies TDP-43 proteinopathies, well frontal cortex 3 normal neurology no or only few deposits. observed three folds, clear relationships between folds diseases. correlated presence 29-kDa sarkosyl-insoluble fragment globular cytoplasmic inclusions, detected an antibody specific carboxy-terminal region TMEM106B. The identification brains older, but not younger, indicates they manner.

Language: Английский

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Cellular and pathological heterogeneity of primary tauopathies

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Aug. 23, 2021

Abstract Microtubule-associated protein tau is abnormally aggregated in neuronal and glial cells a range of neurodegenerative diseases that are collectively referred to as tauopathies. Multiple studies have suggested pathological species may act seed promotes aggregation endogenous naïve contributes propagation pathology. While they share common feature, tauopathies distinct from one another with respect predominant isoforms accumulate the selective vulnerability brain regions cell types inclusions. For instance, primary present pathology, while it mostly Alzheimer’s disease (AD). Also, morphologies inclusions can greatly vary even within same type, suggesting mechanisms or conformers each tauopathy. Neuropathological heterogeneity across challenges our understanding pathophysiology behind seeding aggregation, well efforts develop effective therapeutic strategies for AD other In this review, we describe diverse neuropathological features discuss what has been learned experimental mouse models, advanced transcriptomics, cryo-electron microscopy (cryo-EM) on biology underlying type-specific

Language: Английский

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Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43

Nature, Journal Year: 2022, Volume and Issue: 605(7909), P. 304 - 309

Published: March 28, 2022

Language: Английский

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