Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease

Abstract

Protein homeostasis (Proteostasis) is essential for correct and efficient protein function within the living cell. Among the critical components of the Proteostasis Network (PN) are molecular chaperones that serve widely in protein biogenesis under physiological conditions, and prevent protein misfolding and aggregation enhanced by conditions of cellular stress. For Alzheimer's, Parkinson's, Huntington's diseases and ALS, multiple classes of molecular chaperones interact with the highly aggregation-prone proteins amyloid-β, tau, α-synuclein, huntingtin and SOD1 to influence the course of proteotoxicity associated with these neurodegenerative diseases. Accordingly, overexpression of molecular chaperones and induction of the heat shock response have been shown to be protective in a wide range of animal models of these diseases. In contrast, for cancer cells the upregulation of chaperones has the undesirable effect of promoting cellular survival and tumor growth by stabilizing mutant oncoproteins. In both situations, physiological levels of molecular chaperones eventually become functionally compromised by the persistence of misfolded substrates, leading to a decline in global protein homeostasis and the dysregulation of diverse cellular pathways. The phenomenon of chaperone competition may underlie the broad pathology observed in aging and neurodegenerative diseases, and restoration of physiological protein homeostasis may be a suitable therapeutic avenue for neurodegeneration as well as for cancer.

Keywords: Molecular chaperones; Neurodegenerative diseases; Protein misfolding; Proteostasis.

Fig. 4.1

Schematic reaction of amyloid formation indicating where chaperones act to prevent protein misfolding in the case of amyloid-β, tau, α-synuclein, polyglutamine expansion proteins and/or SOD1. Inhibition of primary nucleation is inferred from the binding of chaperones to the monomeric proteins. Hsp90 alone and with its co-chaperone Aha1 has also been reported to promote aggregation in the case of tau

Fig. 4.2

Aggregate-driven chaperone competition explains the pathological complexity associated with disease-associated aggregation-prone proteins. Shown is a model depicting chaperone competition between protein aggregates and the protein folding and vesicular trafficking arms of the proteostasis network. Under normal conditions (left), Hsc70 is at sufficiently high levels to mediate CME as well as basal protein client folding. Under disease conditions where protein aggregates have accumulated and the Hsc70 relocalizes to aggregates, both protein folding and CME are inhibited (right). This can be reversed by increasing the levels of Hsc70 by small molecule activation of HSF1 to restore chaperone function