Bistability can explain threshold phenomena in protein aggregation both in vitro and in vivo

¹ Northwestern University

^* To whom correspondence should be addressed. E-mail: vassily{at}northwestern.edu.

Submitted on May 15, 2005
Revised on August 3, 2005
Accepted on 25 October 2005

	Abstract

Neurodegenerative disease can originate from the misfolding and aggregation of proteins, such as Amyloid- SOD1,or Huntingtin. Fortunately, all cells possess protein quality control machinery that sequesters misfolded proteins, either refolding or degrading them, before they can self-associate into proteotoxic oligomers and aggregates. This activity is largely performed by the stress response chaperones (i.e. Hsp70). However, the expression level of molecular chaperones can vary widely among cell types. To understand the potential consequence of this variation, we studied the process of protein aggregation in the presence of molecular chaperones using mathematical modeling. We demonstrate that protein aggregation, in the presence of molecular chaperones, is a bistable process. Bistability in protein aggregation offers an explanation for threshold transitions to high aggregate concentration, which are observed both in vitro and in vivo. Additionally, we show that slight variations in chaperone concentration, due to natural fluctuations, have important consequences in a bistable system for the onset of protein aggregation. Therefore, our results offer a possible theoretical explanation for neuronal vulnerability observed in vivo and the onset of neurodegenerative phenotypes in neurons lacking an effective heat shock response.

Key Words: complex systems, multistability, nonlinear dynamics, protein networks, protein quality control, protein triage

This article has been cited by other articles:

				C. G. Evans, S. Wisen, and J. E. Gestwicki Heat Shock Proteins 70 and 90 Inhibit Early Stages of Amyloid beta-(1-42) Aggregation in Vitro J. Biol. Chem., November 3, 2006; 281(44): 33182 - 33191. [Abstract] [Full Text] [PDF]