Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Abstract The assembly of tau into amyloid filaments is associated with more than twenty neurodegenerative diseases, collectively termed tauopathies. Cryo-EM structures brain-derived revealed that specific define different triggering a quest for the development experimental model systems replicate disease. Here, we describe twelve phosphomimetic, serine/threonine to aspartate, mutations in tau, which PAD12, induce vitro full-length same structure as paired helical extracted from brains individuals Alzheimer’s Solution-state nuclear magnetic resonance spectroscopy suggests phosphomimetic carboxy-terminal domain may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 can be used both nucleation-dependent and multiple rounds seeded , well seeding biosensor cells. assembled under various shaking conditions, resulting being stable extended periods time. They labelled fluorophores biotin. Tau disease have been known made hyperphosphorylated abnormally phosphorylated but it was not if presence this post-translational modification mere correlation. Our findings suggest hyperphosphorylation sufficient Alzheimer fold. will useful tool study molecular mechanisms neurodegeneration.

Language: Английский

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Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments

Published: Jan. 16, 2025

The assembly of tau into amyloid filaments is associated with more than twenty neurodegenerative diseases, collectively termed tauopathies. Cryo-EM structures brain-derived revealed that specific define different triggering a quest for the development experimental model systems replicate disease. Here, we describe twelve phosphomimetic, serine/threonine to aspartate, mutations in tau, which PAD12, induce vitro full-length same structure as paired helical extracted from brains individuals Alzheimer’s Solution-state nuclear magnetic resonance spectroscopy suggests phosphomimetic carboxy-terminal domain may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 can be used both nucleation-dependent and multiple rounds seeded , well seeding biosensor cells. assembled under various shaking conditions, resulting being stable extended periods time. They labelled fluorophores biotin. Tau disease have been known made hyperphosphorylated abnormally phosphorylated but it was not if presence this post-translational modification mere correlation. Our findings suggest hyperphosphorylation sufficient Alzheimer fold. will useful tool study molecular mechanisms neurodegeneration.

Language: Английский

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Functional classification of tauopathy strains reveals the role of protofilament core residues

Science Advances, Journal Year: 2025, Volume and Issue: 11(4)

Published: Jan. 22, 2025

Distinct tau amyloid assemblies underlie diverse tauopathies but defy rapid classification. Cell and animal experiments indicate functions as a prion, different strains propagated in cells cause unique, transmissible neuropathology after inoculation. Strain amplification requires compatibility of the monomer template. We used cryo–electron microscopy to study one cell-based yellow fluorescent protein (YFP)–tagged strain, resolving its nature. then sequential alanine (Ala) substitution (scan) within repeat domain (RD) measure incorporation preexisting RD-YFP aggregates. This robustly discriminated strains, defining sequences critical for incorporation. created 3R/4R or 4R wild-type RD (amino acids 246 408) biosensors. Ala scan recombinant seeds with Alzheimer’s disease (AD) fold matched that AD homogenate. scanned 22 brain lysates comprising four tauopathies. clustered cases by neuropathological syndrome, revealed role amino protofilament folds, allowed strain discrimination based on acid requirements prion replication.

Language: Английский

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Cotadutide reversible self-assembly based long-acting injectable depot for sustained delivery of GLP-1 glucagon receptor agonists with controlled burst release

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 380, P. 647 - 663

Published: Feb. 17, 2025

Language: Английский

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Structural and Functional Versatility of the Amyloidogenic Antimicrobial Peptide Citropin 1.3

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Citropin 1.3 is an antimicrobial peptide produced by the amphibian Litoria citropa (Southern bell frog), which self-aggregates into distinct fibrillar structures, however, function of fibrils remains unclear and largely unexplored. In this study, structural functional properties citropin were investigated using cryogenic electron microscopy fluorescence in presence membrane cell models, with X-ray crystallography. Canonical amyloids, multilayered nanotubes, a novel mixed fibril observed. Experiments negatively charged giant unilamellar vesicles revealed that facilitates fusion while simultaneously undergoing phase separation phospholipids. mammalian cells, permeabilizes membranes, leading to death, over time, colocalizes genetic material. Overall, work provides new insights dynamics amyloidogenic its interactions different systems.

Language: Английский

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