Modulation of α-synuclein aggregation amid diverse environmental perturbation DOI Open Access
Abdul Wasim, Sneha Menon, Jagannath Mondal

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: April 2, 2024

Intrinsically disordered protein α-synuclein (αS) is implicated in Parkinson’s disease due to its aberrant aggregation propensity. In a bid identify the traits of aggregation, here we computationally simulate multi-chain association process αS aqueous as well under diverse environmental perturbations. particular, and varied condition led marked concentration differences within aggregates, resembling liquid-liquid phase separation (LLPS). Both saline crowded settings enhanced LLPS However, surface tension droplet responds differently crowders (entropy-driven) salt (enthalpy-driven). Conformational analysis reveals that IDP chains would adopt extended conformations aggregates maintain mutually perpendicular orientations minimize inter-chain electrostatic repulsions. The stability found stem from diminished intra-chain interactions C-terminal regions αS, fostering residue-residue interactions. Intriguingly, graph theory identifies small-world-like networks droplets across conditions, suggesting prevalence consensus interaction patterns among chains. Together these findings suggest delicate balance between molecular grammar environment-dependent nuanced behavior αS.

Language: Английский

Protein misfolding and amyloid nucleation through liquid–liquid phase separation DOI
S. Mukherjee, Manisha Poudyal, K. Dave

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4976 - 5013

Published: Jan. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Language: Английский

Citations

25
Liquid–liquid phase separation in Alzheimer’s disease DOI
Qinggang Fu, Bixiang Zhang,

Xiaoping Chen

et al.

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(2), P. 167 - 181

Published: Jan. 2, 2024

Language: Английский

Citations

10
神经退行性疾病相关淀粉样蛋白的液-液相分离 DOI

Yun-Yi Luo,

Yanmei Li

Chinese Science Bulletin (Chinese Version), Journal Year: 2025, Volume and Issue: 70(7), P. 850 - 859

Published: Feb. 12, 2025

Citations

1
Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations DOI Creative Commons
Beata Szała-Mendyk, Tien M. Phan, Priyesh Mohanty

et al.

Current Opinion in Chemical Biology, Journal Year: 2023, Volume and Issue: 75, P. 102333 - 102333

Published: May 31, 2023

Language: Английский

Citations

17
Amyloid Aggregation and Liquid–Liquid Phase Separation from the Perspective of Phase Transitions DOI
Zhenzhen Zhang, Gangtong Huang, Zhiyuan Song

et al.

The Journal of Physical Chemistry B, Journal Year: 2023, Volume and Issue: 127(28), P. 6241 - 6250

Published: July 6, 2023

Amyloid aggregation describes the aberrant self-assembly of peptides into ordered fibrils characterized by cross-β spine cores and is associated with many neurodegenerative diseases Type 2 diabetes. Oligomers, populated during early stage aggregation, are found to be more cytotoxic than mature fibrils. Recently, amyloidogenic have been reported undergo liquid–liquid phase separation (LLPS)─a biological process important for compartmentalization biomolecules in living cells─prior fibril formation. Understanding relationship between LLPS amyloid especially formation oligomers, essential uncovering disease mechanisms mitigating toxicity. In this Perspective, available theories models first briefly reviewed. By drawing analogies gas, liquid, solid phases thermodynamics, a diagram protein monomer, droplet, states separated coexistence lines can inferred. Due high free energy barrier fibrillization kinetically delaying seeds out droplets, "hidden" monomer-droplet line extends phase. then described as equilibration from initial "out-of-equilibrium" state homogeneous solution monomers final equilibrium stable coexisting and/or droplets via metastable or intermediates. The oligomers also discussed. We suggest that droplet should considered future studies which may help better understand develop therapeutic strategies mitigate

Language: Английский

Citations

17
Tyrosine – a structural glue for hierarchical protein assembly DOI
Anton Maraldo, Jelena Rnjak‐Kovacina, Christopher P. Marquis

et al.

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(7), P. 633 - 648

Published: April 22, 2024

Language: Английский

Citations

8
Aggregation and phase separation of α-synuclein in Parkinson’s disease DOI

W. Han,

Mengrui Wei,

Fei Xu

et al.

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(52), P. 6581 - 6590

Published: Jan. 1, 2024

The deposition of α-synuclein (α-Syn) in Lewy bodies serves as a prominent pathological hallmark Parkinson's disease (PD). Recent research has revealed that α-Syn can undergo liquid-liquid phase separation (LLPS) during its fibrillization. Over time, the maturation resulting condensates leads to liquid-to-solid transition (LSPT) ultimately amyloid cells which is linked pathogenesis and development PD. Herein, we summarize understanding aggregation be described by nucleation elongation steps obtain insights into correlation protein aggregation, structural polymorphism, PD progression. Additionally, discuss LLPS phenomena heterotypic cross-amyloid interactions with focus on aberrant LSPT process. Exploring underlying mechanisms interplay between transitions, will shed light potential therapeutic interventions.

Language: Английский

Citations

5
Liquid–liquid phase separation induced by crowding condition affects amyloid-β aggregation mechanism DOI

Ryuki Kobayashi,

Hideki Nabika

Soft Matter, Journal Year: 2024, Volume and Issue: 20(27), P. 5331 - 5342

Published: Jan. 1, 2024

Liquid–liquid phase separation induced by crowding condition affects the localization and fibril formation of amyloid-β.

Language: Английский

Citations

5
Liquid–liquid phase separation of alpha‐synuclein increases the structural variability of fibrils formed during amyloid aggregation DOI Open Access
Mantas Žiaunys, Darius Šulskis, Dominykas Veiveris

et al.

FEBS Journal, Journal Year: 2024, Volume and Issue: 291(20), P. 4522 - 4538

Published: Aug. 8, 2024

Protein liquid-liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process amyloid fibril formation, serving as an intermediate step between native protein transition into their aggregated state. The formation fibrils via LLPS demonstrated for number proteins related to neurodegenerative disorders, well other amyloidoses. Despite surge amyloid-related studies, influence end-point characteristics still far from fully understood. work, we compare alpha-synuclein aggregation under different conditions, which promote or negate its and examine differences formed aggregates. We show that generates wide variety assemblies with distinct secondary structures morphologies. LLPS-induced also possess higher levels toxicity cells, indicating may be critical appearance disease-related variants.

Language: Английский

Citations

5
Liquid–Liquid Phase Separation (LLPS)-Driven Fibrilization of Amyloid-β Protein DOI

S. Swathi,

Anagha Manohar,

Ethayaraja Mani

et al.

ACS Chemical Neuroscience, Journal Year: 2023, Volume and Issue: 14(19), P. 3655 - 3664

Published: Sept. 18, 2023

Amyloid-β [Aβ(1-40)] aggregation into a fibrillar network is one of the major hallmarks Alzheimer's disease (AD). Recently, few studies reported that polyphosphate (polyP), an anionic biopolymer participates in various cellular physiological processes humans, induces fibrilization many amyloidogenic proteins [ 2020 Disease Facts and Figures; John Wiley Sons Inc., 2020; Tanzi, R. E.; Bertram, L. Cell 2005, 120, 545-555; Selkoe, D. J. Proc. Natl. Acad. Sci. U.S.A. 1995, 275, 630-631; Rambaran, N.; Serpell, C. Prion 2008, 2, 112-117]. However, role polyP Aβ(1-40) underlying mechanism are unclear. In this study, we report experimental investigations on kinetics Aβ(1-40). It found exhibits dual effect depending upon pH value. At = 7 (neutral), inhibits amyloid dose-dependent manner similar to negatively charged nanoparticles. On contrary, at 3 (acidic), accelerates via liquid-liquid phase separation (LLPS), wherein protein-rich droplets contain mature fibrils. parameter space spanned by concentrations polyP, diagram constructed demark domain where LLPS observed 3. Characterization protein aggregates, secondary structure content cell viability presence aggregates discussed both values. This study reveals biopolymers can modulate kinetics, linked neurodegenerative diseases, their local pH.

Language: Английский

Citations

12