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-assoc. into proteotoxic oligomers and aggregates. This activity is largely performed by the stress response chaperones (i.e., Hsp70). However, the expression level of mol. 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 mol. chaperones using math. modeling. We demonstrate that protein aggregation, in the presence of mol. chaperones, is a bistable process. Bistability in protein aggregation offers an explanation for threshold transitions to high aggregate concn., which are obsd. both in vitro and in vivo. Addnl., we show that slight variations in chaperone concn., due to natural fluctuations, have important consequences in a bistable system for the onset of protein aggregation. Therefore, our results offer a possible theor. explanation for neuronal vulnerability obsd. in vivo and the onset of neurodegenerative phenotypes in neurons lacking an effective heat-shock response. [on SciFinder (R)]