Current Concepts of Mixed Pathologies in Neurodegenerative Diseases DOI Creative Commons
Shelley L. Forrest, Gábor G. Kovács

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, Journal Year: 2022, Volume and Issue: 50(3), P. 329 - 345

Published: March 31, 2022

ABSTRACT: Neurodegenerative diseases are a pathologically, clinically and genetically diverse group of disorders without effective disease-modifying therapies. Pathologically, these characterised by disease-specific protein aggregates in neurons and/or glia referred to as proteinopathies. Many neurodegenerative show pathological overlap with the same abnormally deposited occurring anatomically distinct regions, which give rise specific patterns cognitive motor clinical phenotypes. Sequential distribution inclusions throughout brain have been described. Rather than isolation, it is increasingly recognised that combinations one or more proteinopathies cerebrovascular disease frequently occur individuals diseases. In addition, complex constellations ageing-related incidental pathologies associated tau, TDP-43, Aβ, α-synuclein deposition commonly reported longitudinal ageing studies. This review provides an overview current classification age-related presents spectrum complexity mixed community-based, studies, major proteinopathies, genetic conditions. Mixed >65 years impairment; however, they younger (<65 years). thought lower threshold for developing impairment dementia. Hereditary also range beyond proteinopathy primarily linked abnormality. Cases might different course, has prognostic relevance obvious implications biomarker therapy development, stratifying patients trials.

Language: Английский

The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

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

Published: Nov. 13, 2023

Language: Английский

Citations

227
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy DOI Creative Commons
Sofia Lövestam,

Fujiet Adrian Koh,

Bart van Knippenberg

et al.

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

Citations

203
Age-dependent formation of TMEM106B amyloid filaments in human brains DOI Creative Commons
Manuel Schweighauser, Diana Arseni, Mehtap Bacioglu

et al.

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

Citations

142
Alzheimer's disease: From immunotherapy to immunoprevention DOI Creative Commons
Mathias Jucker, Lary C. Walker

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4260 - 4270

Published: Sept. 1, 2023

Language: Английский

Citations

125
Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids DOI
Sjors H. W. Scheres, Benjamin Falcon, Michel Goedert

et al.

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

Published: Sept. 27, 2023

Language: Английский

Citations

110
2.7 Å cryo-EM structure of ex vivo RML prion fibrils DOI Creative Commons
Szymon W. Manka, Wenjuan Zhang,

Adam Wenborn

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: July 13, 2022

Mammalian prions propagate as distinct strains and are composed of multichain assemblies misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure PrP fibrils in highly infectious rod preparations isolated from the brains RML prion-infected mice. We found that rods comprise single-protofilament helical amyloid coexist with twisted pairs same protofilaments. Each rung protofilament is formed by single monomer ordered core comprising residues 94-225, which folds to create two asymmetric lobes N-linked glycans glycosylphosphatidylinositol anchor projecting C-terminal lobe. The overall architecture comparable recently reported brain hamsters infected 263K strain. However, there marked conformational variations could result differences sequence and/or represent distinguishing features strains.

Language: Английский

Citations

107
If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline? DOI Creative Commons
Christian Haass, Dennis J. Selkoe

PLoS Biology, Journal Year: 2022, Volume and Issue: 20(7), P. e3001694 - e3001694

Published: July 21, 2022

Strong genetic evidence supports an imbalance between production and clearance of amyloid β-protein (Aβ) in people with Alzheimer disease (AD). Microglia that are potentially involved alternative mechanisms actually integral to the cascade. Fluid biomarkers brain imaging place accumulation Aβ at beginning molecular clinical changes disease. So why have trials anti-amyloid therapies not provided clear-cut benefits patients AD? Can robustly decrease human brain, if so, could this lowering be too little, late? These central questions research on AD being urgently addressed.

Language: Английский

Citations

107
Mechanisms and pathology of protein misfolding and aggregation DOI
Nikolaos Louros, Joost Schymkowitz, Frédéric Rousseau

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

Citations

105
Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases DOI
Dan Li, Cong Liu

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(9), P. 523 - 534

Published: May 30, 2022

Language: Английский

Citations

75
Disease-specific tau filaments assemble via polymorphic intermediates DOI Creative Commons
Sofia Lövestam, David Li,

Jane L. Wagstaff

et al.

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

Citations

74