Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity

Biochemistry
Huy T LamJan Bieschke

Abstract

Protein misfolding results in the accumulation of aggregated β-sheet-rich structures in Parkinson's disease (PD) and Alzheimer's disease. The toxic oligomer hypothesis stipulates that prefibrillar assemblies, such as soluble oligomers or protofibrils, are responsible for the poor prognosis of these diseases. Previous studies demonstrated that a small molecule related to the natural compound orcein, O4, directly binds to amyloid-β fibrils and stabilizes them, accelerating the formation of end-stage mature fibrils. Here we demonstrate a similar phenomenon during O4 treatment of α-synuclein (αsyn) aggregates, the protein responsible for PD pathology. While the drug did not change the kinetics of aggregate formation as measured by the amyloidophilic dye thioflavin T, O4 depleted αsyn oligomers and promoted the formation of sodium dodecyl sulfate and proteinase K resistant aggregates consisting of large fibril clusters. These fibril clusters exhibited reduced toxicity to human neuronal model cells and reduced seeding activity in vitro. The effectiveness of O4 decreased when it was added at later points in the αsyn aggregation pathway, which suggests that the incorporation of O4 into fibril assemblies stabilizes them against chemical...Continue Reading

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Citations

Sep 24, 2016·Brain : a Journal of Neurology·Michel GoedertBenjamin Falcon
Mar 4, 2017·International Journal of Molecular Sciences·Jordi PujolsSalvador Ventura
Aug 2, 2017·The Journal of Biological Chemistry·Harish KumarJayant B Udgaonkar
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Jan 31, 2017·Neural Plasticity·Francesca LonghenaArianna Bellucci
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Mar 16, 2017·Translational Neurodegeneration·Patrick SweeneyRobert Hodgson
Apr 28, 2021·Proceedings of the National Academy of Sciences of the United States of America·Xue YangJean Baum
Jun 30, 2021·NPJ Parkinson's Disease·Anthony R BraunJonathan N Sachs

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