期刊
NEUROBIOLOGY OF DISEASE
卷 43, 期 3, 页码 715-724出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.05.025
关键词
Parkinson's disease; alpha-Synuclein; Mutations; Oligomers; Electron microscopy; Atomic force microscopy
资金
- Knowledge Cluster Initiative
- Ministry of Health, Labor, and Welfare, Japan
- Alumni Association of the Department of Medicine at Showa University
- Kanae Foundation for the Promotion of Medical Science
- Nagao Memorial fund
- Grants-in-Aid for Scientific Research [22790815] Funding Source: KAKEN
Lewy bodies composed of aggregates of alpha-synuclein (alpha S) in the brain are the main histopathological features of Lewy body diseases (LBD) such as Parkinson's disease and dementia with Lewy bodies. Mutations such as E46K, A30P and A53T in the alpha S gene cause autosomal dominant LBD in a number of kindreds. Although these mutations accelerate fibril formation, their precise effects at early stages of the alpha S aggregation process remain unknown. To answer this question, we examined the aggregation including monomer conformational dynamics and oligomerization of the E46K, A30P, A53T and A30P/A53T mutations and wild type (WT) using thioflavin S assay, circular dichroism spectroscopy, photo-induced cross-linking of unmodified proteins, electron microscopy, and atomic force microscopy. Relative to WT alpha S, E46K alpha S accelerated the kinetics of the secondary structure change and oligomerization, whereas A30P alpha S decelerated them. These effects were reflected in changes in average oligomer size. The mutant oligomers of E46K alpha S functioned as fibril seeds significantly more efficiently than those of WT alpha S, whereas the mutant oligomers of A30P alpha S were less efficient. Our results that mutations of familial LBD had opposite effects at early stages of alpha S assembly may provide new insight into the molecular mechanisms of LBD. (C) 2011 Elsevier Inc. All rights reserved.
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