Liquid–liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson’s disease pathogenesis DOI Creative Commons

Eva D. Ruiz-Ortega,

Anna Wilkaniec, Agata Adamczyk

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Oct. 23, 2024

Parkinson’s disease (PD) and other synucleinopathies are characterized by the aggregation deposition of alpha-synuclein ( α -syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) neurites (LNs). The -syn is a complex process involving structural conversion from its native random coil to well-defined secondary structures rich β -sheets, amyloid-like fibrils. Evidence suggests that intermediate species aggregates formed during this responsible for cell death. However, molecular events involved relationship with onset progression remain not fully elucidated. Additionally, clinical pathological heterogeneity observed various has been highlighted. Liquid–liquid phase separation (LLPS) condensate formation have proposed alternative mechanisms could underpin pathology contribute seen synucleinopathies. This review focuses on role cellular environment conformational rearrangement, which may lead existence different strains varying toxicity patterns. discussion will include stress, abnormal LLPS formation, potential pathology.

Language: Английский

Green tea polyphenol EGCG acts differentially on end-stage amyloid polymorphs of α-synuclein formed in different polyol osmolytes DOI

Santosh Devi,

Dushyant Kumar Garg, Rajiv Bhat

et al.

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2025, Volume and Issue: unknown, P. 141073 - 141073

Published: April 1, 2025

Language: Английский

Citations

0
Biomaterial–tight junction interaction and potential impacts DOI
Xiangfei Han, Ershuai Zhang, Yuanjie Shi

et al.

Journal of Materials Chemistry B, Journal Year: 2019, Volume and Issue: 7(41), P. 6310 - 6320

Published: Jan. 1, 2019

Biomaterial–tight junction (TJ) interactions: analyses of the TJ structure and natural modulation, interaction mechanism, potential impact measuring methods.

Language: Английский

Citations

29
Molecular properties and diagnostic potential of monoclonal antibodies targeting cytotoxic α-synuclein oligomers DOI Creative Commons

Janni Nielsen,

Johanne Lauritsen,

Jannik Nedergaard Pedersen

et al.

npj Parkinson s Disease, Journal Year: 2024, Volume and Issue: 10(1)

Published: July 29, 2024

Abstract α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different ranging from unmodified αSOs species stabilized by lipid peroxidation products polyphenols, formed C-terminally truncated α-syn, multivalent display on capsid virus-like particles (cVLPs). While mAbs generally show a preference for they bind fibrils, variable extents. Overall, observe great diversity in mAbs’ relative affinities monomers varied requirements C-terminal extension only modest effect fibrillation. Several several orders magnitude over in-solution studies, while commercial antibody MJF14 bound 10-fold strongly monomeric α-syn. Gratifyingly, seven almost completely αSO permeabilization membrane vesicles. Five selected identified α-syn-related pathologies like Lewy bodies (LBs) Neurites, well Glial Cytoplasmic Inclusions postmortem brains people diagnosed PD, dementia with LBs or multiple system atrophy, although Three were particularly useful pathological evaluation brain human tissue, including early stages PD. Although there was no straightforward connection between biophysical immunohistochemical properties, it is encouraging that this comprehensive collection able recognize aggregated vitro holds diagnostic potential.

Language: Английский

Citations

2
14-3-3τ as a Modulator of Early α-Synuclein Multimerization and Amyloid Formation DOI Creative Commons
Gobert Heesink, Maxime C. M. van den Oetelaar, Slav A. Semerdzhiev

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1926 - 1936

Published: April 18, 2024

The aggregation of α-synuclein (αS) plays a key role in Parkinson's disease (PD) etiology. While the onset PD is age-related, cellular quality control system appears to regulate αS throughout most human life. Intriguingly, protein 14-3-3τ has been demonstrated delay and various models. However, molecular mechanisms behind this remain elusive. Our study confirms by 14-3-3τ, unveiling concentration-dependent relation. Utilizing microscale thermophoresis (MST) single-molecule burst analysis, we quantified early multimers concluded that these exhibit properties classify them as nanoscale condensates form cooperative process, preceding critical nucleus for fibril formation. Significantly, multimer formation mechanism changes dramatically presence scaffold 14-3-3τ. data modeling suggests modulates multimerization leading creation mixed or co-condensates, comprising both These noncooperative process. They are smaller, more numerous, distinctively not on pathway amyloid Importantly, thus acts very stage multimerization, ensuring does aggregate but remains soluble functional. This offers long-sought novel entries pharmacological modulation PD.

Language: Английский

Citations

1
Liquid–liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson’s disease pathogenesis DOI Creative Commons

Eva D. Ruiz-Ortega,

Anna Wilkaniec, Agata Adamczyk

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Oct. 23, 2024

Parkinson’s disease (PD) and other synucleinopathies are characterized by the aggregation deposition of alpha-synuclein ( α -syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) neurites (LNs). The -syn is a complex process involving structural conversion from its native random coil to well-defined secondary structures rich β -sheets, amyloid-like fibrils. Evidence suggests that intermediate species aggregates formed during this responsible for cell death. However, molecular events involved relationship with onset progression remain not fully elucidated. Additionally, clinical pathological heterogeneity observed various has been highlighted. Liquid–liquid phase separation (LLPS) condensate formation have proposed alternative mechanisms could underpin pathology contribute seen synucleinopathies. This review focuses on role cellular environment conformational rearrangement, which may lead existence different strains varying toxicity patterns. discussion will include stress, abnormal LLPS formation, potential pathology.

Language: Английский

Citations

1