气候变化领域集成服务门户(CCPortal): Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans

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DOI	10.1073/pnas.2021888118
	Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans
	Sinnige T.; Meisl G.; Michaels T.C.T.; Vendruscolo M.; Knowles T.P.J.; Morimoto R.I.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Protein aggregation is associated with a wide range of degenerative human diseases with devastating consequences, as exemplified by Alzheimer's, Parkinson's, and Huntington's diseases. In vitro kinetic studies have provided a mechanistic understanding of the aggregation process at the molecular level. However, it has so far remained largely unclear to what extent the biophysical principles of amyloid formation learned in vitro translate to the complex environment of living organisms. Here, we take advantage of the unique properties of a Caenorhabditis elegans model expressing a fluorescently tagged polyglutamine (polyQ) protein, which aggregates into discrete micrometer-sized inclusions that can be directly visualized in real time. We provide a quantitative analysis of protein aggregation in this system and show that the data are described by a molecular model where stochastic nucleation occurs independently in each cell, followed by rapid aggregate growth. Global fitting of the imagebased aggregation kinetics reveals a nucleation rate corresponding to 0.01 h-1per cell at 1 mM intracellular protein concentration, and shows that the intrinsic molecular stochasticity of nucleation accounts for a significant fraction of the observed animal-to-animal variation. Our results highlight how independent, stochastic nucleation events in individual cells control the overall progression of polyQ aggregation in a living animal. The key finding that the biophysical principles associated with protein aggregation in small volumes remain the governing factors, even in the complex environment of a living organism, will be critical for the interpretation of in vivo data from a wide range of protein aggregation diseases. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Amyloid; C. elegans; Chemical kinetics; Polyglutamine; Protein aggregation
语种	英语
scopus关键词	cell protein; fluorescent dye; polyglutamine; Article; Caenorhabditis elegans; cell level; development; disease association; fluorescence analysis; mathematical model; muscle cell; nonhuman; nucleation; priority journal; protein aggregation; protein expression; protein structure; quantitative analysis
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180235
作者单位	Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208-3500, United States; Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, United Kingdom; Cavendish Laboratory, University of Cambridge, Cambridge, CB3 0HE, United Kingdom
推荐引用方式 GB/T 7714	Sinnige T.,Meisl G.,Michaels T.C.T.,et al. Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans[J],2021,118(11).
APA	Sinnige T.,Meisl G.,Michaels T.C.T.,Vendruscolo M.,Knowles T.P.J.,&Morimoto R.I..(2021).Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Sinnige T.,et al."Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).