Polyglutamine Aggregation in a Living Animal is Governed by Biophysical Parameters

Abstract

Protein misfolding and aggregation are a hallmark of a variety of human diseases. The misfolding of proteins into amyloid fibrils has been studied extensively in vitro, leading to a detailed description of the aggregation kinetics of several disease-associated proteins and peptides. However, it is unclear if the same principles are sufficient to explain the accumulation of protein aggregates in living cells and organisms. In particular, it has become clear that protein homeostasis declines with organismal age, making proteins more susceptible to undergo irreversible conformational changes into an aggregated state at older age. Using the nematode worm Caenorhabditis elegans as a model organism, we have characterized the aggregation kinetics of polyglutamine, which is related to Huntington's and other genetic expansion diseases. We find that the kinetics of polyglutamine aggregation critically depend on parameters including polyglutamine repeat length, temperature and protein concentration. These results indicate that the aggregation kinetics of polyglutamine in a living animal are largely governed by the same biophysical parameters that underly this process in vitro. However, the aggregation curves have to be interpreted as a superposition of the events occurring in individual cells, leading us to prose a model of stochastic nucleation in each cell followed by aggregate growth. Furthermore, we find that the rates of these events are modulated by known genetic modifiers and components of the protein homeostasis network. Altogether our study provides a mechanistic framework for the quantitative understanding of protein aggregation in a living and aging organism, opening up new avenues to address how toxic protein aggregation can be opposed by the action of e.g. molecular chaperones and small molecules.