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 Jjournal_title
Biophysical journalauthors
Rieger TR,Morimoto RI,Hatzimanikatis Vdoi
10.1529/biophysj.105.066662subject
Has Abstractpub_date
2006-02-01 00:00:00pages
886-95issue
3eissn
0006-3495issn
1542-0086pii
S0006-3495(06)72276-7journal_volume
90pub_type
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