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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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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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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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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Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Cell, Journal Year: 2022, Volume and Issue: 185(8), P. 1346 - 1355.e15

Published: March 4, 2022

Misfolding and aggregation of disease-specific proteins, resulting in the formation filamentous cellular inclusions, is a hallmark neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that previously unsolved amyloid fibril composed 135 amino acid C-terminal fragment TMEM106B common finding distinct human diseases, including cases characterized by abnormal TDP-43, tau, α-synuclein protein. A combination cryoelectron microscopy mass spectrometry was used to solve structures fibrils at resolution 2.7 Å from postmortem brain tissue afflicted frontotemporal lobar degeneration TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, 2), dementia Lewy bodies (DLB, 1). The commonality abundant TMEM106B, lysosomal/endosomal protein, broad range debilitating disorders indicates shared fibrillization pathway may initiate accelerate neurodegeneration.

Language: Английский

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Liquid-Liquid Phase Separation of TDP-43 and FUS in Physiology and Pathology of Neurodegenerative Diseases

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: Feb. 2, 2022

Liquid-liquid phase separation of RNA-binding proteins mediates the formation numerous membraneless organelles with essential cellular function. However, aberrant transition these leads to insoluble protein aggregates, which are pathological hallmarks neurodegenerative diseases including ALS and FTD. TDP-43 FUS two such that mislocalize aggregate in patients They have similar domain structures provide multivalent interactions driving their vitro environment. In this article, we review factors mediate regulate FUS. We also evidences connect property functional roles cells. Aberrant aggregation disrupts regular cell Therefore, restoration could be beneficial for neuronal discuss possible mechanisms while reviewing methods currently being explored as potential therapeutic strategies mitigate

Language: Английский

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Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson’s disease and other synucleinopathies

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: July 22, 2022

Abstract Parkinson’s disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10–15 years before clinical diagnostic symptoms of are manifested. Furthermore, several aspects PD pathology overlap with other diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need discover validate early prognostic markers that reflect pathophysiology, progression, severity, potential differences in mechanisms between NDDs. The close association aSyn development synucleinopathies, along identification species biological fluids, has led increasing interest as biomarkers diagnosis differentiate it from In this review, we (1) provide overview progress toward mapping distribution brain, peripheral tissues, fluids; (2) present comparative critical analysis previous studies measured total well such modified aggregated forms different (3) highlight conceptual technical gaps challenges could hinder validation reliable biomarkers; (4) outline a series recommendations address these challenges. Finally, propose combined biomarker approach based on integrating biochemical, aggregation structure features aSyn, addition neurodegeneration. We believe capturing diversity essential develop robust assays diagnostics detection, patient stratification, monitoring differentiation This transform trial design implementation, accelerate new therapies, improve decisions treatment strategies.

Language: Английский

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The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(10), P. 1340 - 1349

Published: Sept. 25, 2023

The maturation of liquid-like protein condensates into amyloid fibrils has been associated with several neurodegenerative diseases. However, the molecular mechanisms underlying this liquid-to-solid transition have remained largely unclear. Here we analyse formation mediated by condensation low-complexity domain hnRNPA1, a involved in amyotrophic lateral sclerosis. We show that phase separation and fibrillization are connected but distinct processes modulated different regions sequence. By monitoring spatial temporal evolution demonstrate does not occur homogeneously inside droplets is promoted at interface condensates. further coating surfactant molecules inhibits fibril formation. Our results reveal biomolecular hnRNPA1 promotes formation, therefore suggesting interfaces as potential novel therapeutic target against aberrant amyloids condensation.

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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TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 898 - 903

Published: Aug. 2, 2023

Abstract The abnormal assembly of TAR DNA-binding protein 43 (TDP-43) in neuronal and glial cells characterizes nearly all cases amyotrophic lateral sclerosis (ALS) around half frontotemporal lobar degeneration (FTLD) 1,2 . A causal role for TDP-43 neurodegeneration is evidenced by dominantly inherited missense mutations TARDBP , the gene encoding TDP-43, that promote give rise to ALS FTLD 3–7 At least four types (A–D) with pathology (FTLD-TDP) are defined distinct brain distributions assembled associated different clinical presentations dementia 8 We previously showed, using cryo-electron microscopy, assembles into amyloid filaments type B FTLD-TDP 9 However, structures without remained unknown. Here we report microscopy from brains three individuals most common FTLD-TDP, A. formed a new fold was same across individuals, indicating this may characterize FTLD-TDP. resembles chevron badge unlike double-spiral-shaped establishing filament folds neurodegenerative conditions. structures, combination mass spectrometry, led identification two post-translational modifications citrullination monomethylation R293, indicate they facilitate formation observed structural variation individual filaments. will guide mechanistic studies assembly, as well development diagnostic therapeutic compounds proteinopathies.

Language: Английский

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