期刊
ACS NANO
卷 13, 期 3, 页码 3232-3242出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b08932
关键词
Parkinson's disease; VCD; amyloid peptide; handedness inversion; helical structures; peptide self-assembly
类别
资金
- Natural Sciences and Engineering Research Council (NSERC) of Canada
- Fonds de recherche du Quebec-Nature et Technologies (FRQ-NT)
- Universite Laval
- FRQ-NT
- Bionano (NSERC)
- PROTEO
- Centre National de Recherche Scientifique (CNRS, Chemistry Department)
- Region Aquitaine
Parkinson's disease is an incurable neurodegenerative disorder caused by the aggregation of alpha-synuclein (AS). This amyloid protein contains a 12-residue-long segment, AS(71-82), that triggers AS pathological aggregation. This peptide is then essential to better understand the polymorphism and the dynamics of formation of AS fibrillar structures. In this work, vibrational circular dichroism showed that AS(71-82) is random coil in solution and forms parallel beta-sheet fibrillar aggregates in the presence of anionic vesicles. Vibrational circular dichroism, with transmission electronic microscopy, revealed that the fibrillar structures exhibit a nanoscale tape-like morphology with a preferential supramolecular helicity. Whereas the structure handedness of some other amyloid peptides has been shown to be driven by pH, that of AS(71-82) is controlled by peptide concentration and peptide-to-lipid (P:L) molar ratio. At low concentrations and low P:L molar ratios, AS(71-82) assemblies have a left-twisted handedness, whereas at high concentrations and high P:L ratios, a right-twisted handedness is adopted. Left-twisted assemblies interconvert into right-twisted ones with time, suggesting a maturation of the amyloid structures. As fibril species with two chiralities have also been reported previously in Parkinson's disease Lewy bodies and fibrils, the present results seem relevant to better understand AS amyloid assembly and fibrillization in vivo. From a diagnosis or therapeutic point of view, it becomes essential that future fibril probes, inhibitors, or breakers target pathological assemblies with specific chirality and morphology, in particular, because they may change with the stage of the disease.
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