Bistability explains threshold phenomena in protein aggregation both in vitro and in vivo.

Abstract:

:Neurodegenerative disease can originate from the misfolding and aggregation of proteins, such as Amyloid-beta, 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 varies 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.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Rieger TR,Morimoto RI,Hatzimanikatis V

doi

10.1529/biophysj.105.066662

subject

Has Abstract

pub_date

2006-02-01 00:00:00

pages

886-95

issue

3

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(06)72276-7

journal_volume

90

pub_type

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