Kinetic analysis reveals that independent nucleation events determine the progression of polyglutamine aggregation in C. elegans

Tessa Sinnige*, Georg Meisl, Thomas C.T. Michaels, Michele Vendruscolo, Tuomas P.J. Knowles, Richard I. Morimoto

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere2021888118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • Amyloid
  • C. elegans
  • Chemical kinetics
  • Polyglutamine
  • Protein aggregation

ASJC Scopus subject areas

  • General

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