期刊
BIOCHEMISTRY
卷 55, 期 4, 页码 675-685出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.5b01168
关键词
-
资金
- DRC at Washington University (National Institutes of Health) [5 P30 DK020579]
- German Science Foundation (DFG) [BI 1409/1-1]
- German Ministry for Science and Education (BMBF) [NGFN-Plus 01GS08132, GERAMY 01GM1107C]
Protein misfolding results in the accumulation of aggregated beta-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-beta fibrils and stabilizes them, accelerating the formation of end-stage mature fibrils. Here we demonstrate a similar phenomenon during O4 treatment of alpha-synuclein (alpha syn) 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 alpha syn 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 alpha syn aggregation pathway, which suggests that the incorporation of O4 into fibril assemblies stabilizes them against chemical, enzymatic, and mechanic degradation. These findings suggest that small molecules, which stabilize amyloid fibrils, can prevent fibril fragmentation and seeding and consequently prevent prion-like replication of misfolded alpha syn. Inhibiting priori replication by fibril stabilization could thus be a therapeutic strategy for PD.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据