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Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo
Published on: June 2, 2019
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Supramolecular Modulation of Structural Polymorphism in Pathogenic α-Synuclein Fibrils Using Copper(II) Coordination
Tae Su Choi1, Jeeyoung Lee2, Jong Yoon Han1
1Department of Chemistry, Korea University, Seoul, 02841, Republic of Korea.
Angewandte Chemie (International Ed. in English)
|January 26, 2018
Summary
Copper(II) ions promote the formation of shorter, pathogenic alpha-synuclein (αSyn) fibrils. This novel supramolecular approach reveals how physiological factors like brain copper influence αSyn structure and neurotoxicity in synucleinopathies.
Area of Science:
- Biochemistry
- Neuroscience
- Materials Science
Background:
- Structural variations in alpha-synuclein (αSyn) fibrils are implicated in synucleinopathies.
- The precise mechanisms driving the pathogenicity of αSyn fibrils remain largely unknown.
Purpose of the Study:
- To investigate the formation process of pathogenic αSyn fibrils using a copper(II)-based supramolecular approach.
- To elucidate the neurotoxic mechanisms associated with these pathogenic fibrils.
Main Methods:
- Utilized a copper(II) (Cu(II))-based supramolecular strategy to study αSyn fibril formation.
- Analyzed the conformational changes of αSyn monomers induced by Cu(II) macrochelation.
- Compared the characteristics and cellular effects of Cu(II)-induced fibrils with typical αSyn fibrils.
Main Results:
- Cu(II) macrochelation strained αSyn monomers, inhibiting fibril elongation and promoting nucleation.
- This process generated shorter ( <0.2 μm), β-sheet-rich αSyn fibrils.
- These pathogenic fibrils were rapidly transmitted to and accumulated in neuronal cells, inducing cell death, unlike typical longer fibrils (ca. 1 μm).
Conclusions:
- Established a supramolecular basis for pathogenic αSyn fibril formation driven by physiological factors like brain Cu(II).
- Demonstrated a novel mechanism linking copper ions to αSyn pathology and neurotoxicity relevant to synucleinopathies.
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