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Advanced Science

Advanced Science

IF: 14.3
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Single-Molecule Insight Into α-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds

Published:14 February 2025 DOI: 10.1002/advs.202416721 PMID: 39951335
Xiang Li, Lulu Bi, Shenqing Zhang, Qianhui Xu, Wencheng Xia, Youqi Tao, Shaojuan Wu, Yanan Li, Weidong Le, Wenyan Kang, Dan Li, Bo Sun, Cong Liu

Abstract

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

Substances (18)

Materials
Procduct Name CAS Molecular Formula Supplier Price
(-)-Epigallocatechin gallate 989-51-5 C22H18O11 751 suppliers $5.00-$1838.00
(-)-Epigallocatechin gallate 989-51-5 C22H18O11 751 suppliers $5.00-$1838.00
(-)-Epigallocatechin gallate 989-51-5 C22H18O11 751 suppliers $5.00-$1838.00
(-)-Epigallocatechin gallate 989-51-5 C22H18O11 751 suppliers $5.00-$1838.00
Chlorophyllin 11006-34-1 C34H31CuN4NaO6(-2) 386 suppliers $5.00-$1134.35
Chlorophyllin 11006-34-1 C34H31CuN4NaO6(-2) 386 suppliers $5.00-$1134.35
Chlorophyllin 11006-34-1 C34H31CuN4NaO6(-2) 386 suppliers $5.00-$1134.35
Chlorophyllin 11006-34-1 C34H31CuN4NaO6(-2) 386 suppliers $5.00-$1134.35
Chlorophyllin 11006-34-1 - Inquiry
Chlorophyllin 11006-34-1 - Inquiry

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