Interplay between protein homeostasis networks in protein aggregation and proteotoxicity

Abstract

The misfolding and aggregation of disease proteins is characteristic of numerous neurodegenerative diseases. Particular neuronal populations are more vulnerable to proteotoxicity while others are more apt to tolerate the misfolding and aggregation of disease proteins. Thus, the cellular environment must play a significant role in determining whether disease proteins are converted into toxic or benign forms. The endomembrane network of eukaryotes divides the cell into different subcellular compartments that possess distinct sets of molecular chaperones and protein interaction networks. Chaperones act as agonists and antagonists of disease protein aggregation to prevent the accumulation of toxic intermediates in the aggregation pathway. Interacting partners can also modulate the conformation and localization of disease proteins and thereby influence proteotoxicity. Thus, interplay between these protein homeostasis network components can modulate the self-association of disease proteins and determine whether they elicit a toxic or benign outcome.

FIGURE 1

Pathways for the assembly of misfolded proteins into different aggregation states. A native protein can misfold into a nonnative, conformation as a result of mutation or cellular stress. The nonnative monomer is highly unstable and can sample numerous conformations including a β-sheet-rich form. The self-association of the β-sheet-rich monomers can result in a stable protofibril or amyloid seed which can subsequently drive the autocatalytic conversion of protein monomers into the growing amyloid fibril. Alternatively, inefficient flux through amyloid assembly pathways can result in the formation of off-pathway aggregates including amorphous or nonspecific aggregates.