Single‐Molecule Insight Into α‐Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds DOI Creative Commons
Xiang Li, Lulu Bi, Shenqing Zhang

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach developed probe the mechanical characteristics fibrils at single-molecule level. When subjected axial stretching, local deformation within appeared forces above 50 pN. These structural alternations occurred stepwise irreversible, suggesting unfolding individual subdomains. Additionally, exhibits high heterogeneity in lateral disruption, rupture force ranging from 500 The impact different compounds on structure features further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates by wedging into N-terminal polar groove induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches four sites wrapping around core, reinforcing stability against forces. work offers effective method for characterizing single-fibril properties bridges compound-induced response. insights valuable understanding amyloid mechanics their regulation molecules.

Language: Английский

Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions DOI Creative Commons
Grace m. Kuo, Ramhari Kumbhar,

W. Frank Blair

et al.

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 23, 2025

Abstract α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s concurrent with LBD (AD-LBD). These disorders are unified by pathological hallmark: aberrant misfolding accumulation α-synuclein (α-syn). This review delves into the pivotal role α-syn, key agent in α-synucleinopathy pathophysiology, provides survey potential therapeutics that target cell-to-cell spread pathologic α-syn. Recognizing intricate complexity multifactorial etiology α-synucleinopathy, illuminates various membrane receptors, proteins, intercellular spreading pathways, agents for therapeutic interventions. While significant progress has been made understanding pursuit efficacious treatments remains challenging. Several strategies involving decreasing α-syn production aggregation, increasing degradation, lowering extracellular inhibiting cellular uptake presented. The paper underscores necessity meticulous comprehensive investigations to advance our knowledge pathology ultimately develop innovative α-synucleinopathies. Graphical

Language: Английский

Citations

1
Re-examining the pathobiological basis of gait dysfunction in Parkinson’s disease DOI
Newton Cho, Lorraine V. Kalia, Suneil K. Kalia

et al.

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Sex differences for regional pathology in people with a high likelihood of Lewy body dementia phenotype based on underlying pathology DOI Creative Commons
Ece Bayram, David G. Coughlin, Shunsuke Koga

et al.

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 1, 2025

Clinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis regional pathologies. We included 357 people (131 female, 226 male) with a high likelihood of LBD based pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences body, senile plaque, and neurofibrillary tangle counts their associations clinical diagnosis were assessed. Females likely to diagnosis; they had more bodies, tangles, plaques various regions than males (all p's < 0.05). A higher was associated middle frontal, cingulate, entorhinal pathology, so females 0.045). clinicopathological also occur at level. frequency misdiagnosis males. risk underdiagnosis (LBD) males.Regional LBD.Regional association differs sex.Regional stronger phenotype

Language: Английский

Citations

1
The effect of AKT inhibition in α-synuclein-dependent neurodegeneration DOI Creative Commons
Bedri Ranxhi,

Zoya R. Bangash,

Zachary M. Chbihi

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 18

Published: Feb. 5, 2025

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark PD pathology the accumulation α-synuclein (α-Syn), small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes contribute damage neurodegeneration. Previous studies implicated AKT signaling pathway toxicity models suggesting as potential therapeutic target. Here, we investigated effect inhibition Drosophila model synucleinopathy. We observed administration inhibitor, A-443654 led mild improvements both survival motor function flies expressing human α-Syn. Genetic revealed reduction levels decreased levels, concomitant with improved physiological outcomes. The protective effects appear operate through fly ortholog NF-κB, Relish, link between NF-κB regulating levels. These findings highlight cascade target for synucleinopathies provide insights mechanisms could be utilized reduce related disorders, such multiple system atrophy.

Language: Английский

Citations

1
Single‐Molecule Insight Into α‐Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds DOI Creative Commons
Xiang Li, Lulu Bi, Shenqing Zhang

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach developed probe the mechanical characteristics fibrils at single-molecule level. When subjected axial stretching, local deformation within appeared forces above 50 pN. These structural alternations occurred stepwise irreversible, suggesting unfolding individual subdomains. Additionally, exhibits high heterogeneity in lateral disruption, rupture force ranging from 500 The impact different compounds on structure features further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates by wedging into N-terminal polar groove induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches four sites wrapping around core, reinforcing stability against forces. work offers effective method for characterizing single-fibril properties bridges compound-induced response. insights valuable understanding amyloid mechanics their regulation molecules.

Language: Английский

Citations

1