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

Liquid-liquid Phase Separation of α-Synuclein: A New Mechanistic Insight for α-Synuclein Aggregation Associated with Parkinson's Disease Pathogenesis DOI Open Access
Semanti Mukherjee, Arunima Sakunthala, Laxmikant Gadhe

et al.

Journal of Molecular Biology, Journal Year: 2022, Volume and Issue: 435(1), P. 167713 - 167713

Published: July 3, 2022

Language: Английский

Citations

83
Mass photometric detection and quantification of nanoscale α-synuclein phase separation DOI
Soumik Ray, Thomas O. Mason, Lars Boyens‐Thiele

et al.

Nature Chemistry, Journal Year: 2023, Volume and Issue: 15(9), P. 1306 - 1316

Published: June 19, 2023

Language: Английский

Citations

68
Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation DOI
Linwei Yu, Xi Li, Tianyi Shi

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 297, P. 139875 - 139875

Published: Jan. 14, 2025

Language: Английский

Citations

2
Role of aberrant phase separation in pathological protein aggregation DOI
Pijush Chakraborty, Markus Zweckstetter

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 82, P. 102678 - 102678

Published: Aug. 19, 2023

Language: Английский

Citations

38
Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation DOI Creative Commons

Bingkuan Xu,

Fengshuo Fan,

Yunpeng Liu

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(5), P. 726 - 726

Published: April 23, 2023

The Lewy bodies and neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation (LLPS) form amyloid aggregates in a condensate pathway. How PD-associated affect LLPS its correlation aggregation remains incompletely understood. Here, we examined effects five identified PD, A30P, E46K, H50Q, A53T, A53E, on α-Syn. All other mutants behave similarly wild-type (WT) α-Syn, except that E46K mutation substantially promotes condensates. mutant droplets fuse WT recruit monomers into their droplets. Our showed A53T accelerated In contrast, A53E retarded during liquid-to-solid transition. Finally, observed formed condensates cells, whereas apparently promoted These findings reveal have divergent phase-separated condensates, providing new insights pathogenesis mutations.

Language: Английский

Citations

23
Protein–protein interactions regulating α-synuclein pathology DOI
Jiannan Wang,

Lijun Dai,

Sichun Chen

et al.

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(3), P. 209 - 226

Published: Feb. 13, 2024

Language: Английский

Citations

11
Molecular Insights into the Misfolding and Dimerization Dynamics of the Full-Length α-Synuclein from Atomistic Discrete Molecular Dynamics Simulations DOI
Yu Zhang, Ying Wang,

Yuying Liu

et al.

ACS Chemical Neuroscience, Journal Year: 2022, Volume and Issue: 13(21), P. 3126 - 3137

Published: Oct. 24, 2022

The misfolding and pathological aggregation of α-synuclein forming insoluble amyloid deposits is associated with Parkinson's disease, the second most common neurodegenerative disease in world population. Characterizing self-assembly mechanism critical for discovering treatments against synucleinopathies. intrinsically disordered property, high degrees freedom, macroscopic timescales conformational conversion make its characterization extremely challenging vitro silico. Here, we systematically investigated dynamics monomer dimerization full-length using atomistic discrete molecular simulations. Our results suggested that both monomers dimers mainly adopted unstructured formations partial helices around N-terminus (residues 8-32) various β-sheets spanning residues 35-56 (N-terminal tail) 61-95 (NAC region). C-terminus mostly assumed an formation wrapping lateral surface elongation edge β-sheet core formed by N-terminal tail NAC regions. Dimerization enhanced along a decrease content. inter-peptide were NACore 68-78) regions, suggesting these two regions played roles α-synuclein. Interactions region significantly suppressed dimer, indicating interaction could prevent aggregation. These on structural ensembles early will help understand nucleation fibrillization

Language: Английский

Citations

34
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
Liquid–liquid phase separation of α‐synuclein is highly sensitive to sequence complexity DOI
Anindita Mahapatra, Robert W. Newberry

Protein Science, Journal Year: 2024, Volume and Issue: 33(4)

Published: March 21, 2024

The Parkinson's-associated protein α-synuclein (α-syn) can undergo liquid-liquid phase separation (LLPS), which typically leads to the formation of amyloid fibrils. coincidence LLPS and has complicated identification molecular determinants unique α-syn. Moreover, lack strategies selectively perturb makes it difficult dissect biological roles specific α-syn LLPS, independent fibrillation. Herein, using a combination subtle missense mutations, we show that is highly sensitive its sequence complexity. In fact, find even conservative mutation (V16I) increases complexity without perturbing physicochemical structural properties, sufficient reduce by 75%; this effect be reversed an adjacent V-to-I (V15I) restores original A18T, complexity-enhancing PD-associated mutation, was likewise found implicating in pathogenicity. Furthermore, leveraging differences propensities among different variants, demonstrate fibrillation does not necessarily correlate with LLPS. identify mutations or α-syn, unlike previously studied mutations. variants design principles reported herein should therefore empower future studies disentangle these two phenomena distinguish their (patho)biological roles.

Language: Английский

Citations

8
Phase Separation and Aggregation of α‐Synuclein Diverge at Different Salt Conditions DOI Creative Commons
Rebecca Sternke‐Hoffmann,

Xun Sun,

Andreas Menzel

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 7, 2024

The coacervation of alpha-synuclein (αSyn) into cytotoxic oligomers and amyloid fibrils are considered pathological hallmarks Parkinson's disease. While aggregation is central to diseases, liquid-liquid phase separation (LLPS) its interplay with have gained increasing interest. Previous work shows that factors promoting or inhibiting similar effects on LLPS. This study provides a detailed scanning wide range parameters, including protein, salt crowding concentrations at multiple pH values, revealing different dependencies influence under conditions follows non-monotonic pattern, showing increased medium concentrations. behavior can be elucidated through combination electrostatic screening salting-out the intramolecular interactions between N-terminal C-terminal regions αSyn. By contrast, this finds monotonic dependence LLPS due intermolecular interactions. Furthermore, it observes time evolution two distinct assembly states, macroscopic fibrillar-like bundles initially forming concentration but subsequently converting droplets after prolonged incubation. droplet state therefore capable even dissolving aggregates heterotypic interactions, thus preventing αSyn from dynamically arrested state.

Language: Английский

Citations

5