The N-terminal Region of α-Synuclein Controls Amyloid Nucleation at the Condensate Interface DOI Open Access
Rebecca J. Thrush, Devkee M. Vadukul, Siân C. Allerton

et al.

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

Published: June 6, 2024

Abstract α-Synuclein self-assembles into amyloid fibrils during neurodegeneration. The protein can also self-assemble via liquid-liquid phase separation to form biomolecular condensates. link between these processes is evident, as α-synuclein condensates mature amyloids. However, the mechanisms driving this maturation remain largely unknown, particularly when incorporating pathological post-translational modifications known affect self-assembly in absence of LLPS, such N-terminal truncation. Moreover, are primarily studied isolated entities; however, it increasingly evident that they interact with various cellular components and surfaces. Here, we developed a microscopy-based quantitative real-time imaging protocol investigate how truncation influences condensate formation, well surface wetting, maturation. We found increasing truncation, which reduces hydrophobicity, inhibits sedimentation, enhances wettability, accelerates Additionally, by hydrophobicity decreased delaying their Thus, propose enhanced increases surface-to-volume ratio, promotes nucleation at condensate-bulk solution interface, thereby accelerating Our results reveal distinct mechanistic roles for residues indicate wetting on surfaces, synaptic vesicles, may drive toxic aggregate formation

Language: Английский

A single fibril study reveals that ApoE inhibits the elongation of Aβ42 fibrils in an isoform-dependent manner DOI Creative Commons
Sourav Dasadhikari,

Shamasree Ghosh,

Sudip Pal

et al.

Communications Chemistry, Journal Year: 2025, Volume and Issue: 8(1)

Published: April 30, 2025

ApoE-ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), linked to increased amyloid-β (Aβ) deposition in brain. In AD mouse models, microglial expression of apoE3 reduces amyloid plaque burden through enhanced phagocytosis, whereas apoE4 associated with impaired Aβ clearance. However, isoform-specific interactions apoE aggregates and molecular mechanisms by which these isoforms influence aggregation clearance remain poorly understood, critical developing potential therapeutic interventions. Here, we employed TIRFM, superresolution microscopy, single-molecule photobleaching techniques investigate effects on rate constants Aβ42 at single-fibril level, as well quantify binding affinity specificity individual fibril ends. Our results show that ca. 4-5 times less effective than apoE2 inhibiting elongation, while secondary nucleation largely unaffected any isoforms. Furthermore, exhibits stronger more specific ends compared apoE4. These findings suggest apoE4's reduced growing may impair increase a higher elongation brain carriers.

Language: Английский

Citations

0
The thermodynamic hypothesis of protein aggregation DOI Creative Commons
Michele Vendruscolo

Molecular Aspects of Medicine, Journal Year: 2025, Volume and Issue: 103, P. 101364 - 101364

Published: May 3, 2025

Language: Английский

Citations

0
Computational Discovery of Plant-Derived Flavonoids as Potential Amyloid-β Fibril Disaggregating Agents for Alzheimer’s Disease DOI Creative Commons

Uthirapathi Logeswari Rakesh,

Golla Anil Kumar,

Theivendren Panneerselvam

et al.

Brain Disorders, Journal Year: 2025, Volume and Issue: unknown, P. 100233 - 100233

Published: May 1, 2025

Language: Английский

Citations

0
The N-terminal Region of α-Synuclein Controls Amyloid Nucleation at the Condensate Interface DOI Open Access
Rebecca J. Thrush, Devkee M. Vadukul, Siân C. Allerton

et al.

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

Published: June 6, 2024

Abstract α-Synuclein self-assembles into amyloid fibrils during neurodegeneration. The protein can also self-assemble via liquid-liquid phase separation to form biomolecular condensates. link between these processes is evident, as α-synuclein condensates mature amyloids. However, the mechanisms driving this maturation remain largely unknown, particularly when incorporating pathological post-translational modifications known affect self-assembly in absence of LLPS, such N-terminal truncation. Moreover, are primarily studied isolated entities; however, it increasingly evident that they interact with various cellular components and surfaces. Here, we developed a microscopy-based quantitative real-time imaging protocol investigate how truncation influences condensate formation, well surface wetting, maturation. We found increasing truncation, which reduces hydrophobicity, inhibits sedimentation, enhances wettability, accelerates Additionally, by hydrophobicity decreased delaying their Thus, propose enhanced increases surface-to-volume ratio, promotes nucleation at condensate-bulk solution interface, thereby accelerating Our results reveal distinct mechanistic roles for residues indicate wetting on surfaces, synaptic vesicles, may drive toxic aggregate formation

Language: Английский

Citations

0