Chemical and/or biological therapeutic strategies to ameliorate protein misfolding diseases - PubMed (original) (raw)

Review

Chemical and/or biological therapeutic strategies to ameliorate protein misfolding diseases

Derrick Sek Tong Ong et al. Curr Opin Cell Biol. 2011 Apr.

Abstract

Inheriting a mutant misfolding-prone protein that cannot be efficiently folded in a given cell type(s) results in a spectrum of human loss-of-function misfolding diseases. The inability of the biological protein maturation pathways to adapt to a specific misfolding-prone protein also contributes to pathology. Chemical and biological therapeutic strategies are presented that restore protein homeostasis, or proteostasis, either by enhancing the biological capacity of the proteostasis network or through small molecule stabilization of a specific misfolding-prone protein. Herein, we review the recent literature on therapeutic strategies to ameliorate protein misfolding diseases that function through either of these mechanisms, or a combination thereof, and provide our perspective on the promise of alleviating protein misfolding diseases by taking advantage of proteostasis adaptation.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1. The Proteostasis Network

Schematic of the endoplasmic reticulum (ER) proteostasis network in mammalian cells depicting the components and the connections in simplified format. A holdase chaperone delivers the nascent chain to the Hsp-70-40-nucleotide exchange factor pathway and/or the Hsp90-cochaperone pathway and/or the Calnexin-calreticulin pathway which can lead to folding and vesicular trafficking or degradation mediated by ER-associated degradation (proteasome) and/or by autophagy.

Figure 2

Figure 2. Pharmacologic Chaperoning

A small molecule pharmacologic chaperone binds to the folded ensemble of a specific mutant misfolding-prone lysosomal storage disease-associated enzyme in the endoplasmic reticulum (ER) and stabilizes the mutant enzyme. This increases the fraction of folded enzyme that can bind to the trafficking receptor and be trafficked to the lysosome to degrade its substrate.

Figure 3

Figure 3. Adapting the Proteostasis Network

Small molecule proteostasis regulators can induce the unfolded protein response (UPR) transcriptional program leading to the coordinated upregulation of endoplasmic reticulum (ER) proteostasis network capacity. The chaperones, co-chaperones and folding enzymes can resculpt the folding free energy diagram of mutant enzymes, “pushing” more protein toward the native state by lowering the energy of intermediate and transition states and minimizing misfolding. Small molecule proteostasis regulators can also function by post-translation regulation mechanisms. One example are the Ryanodine receptor antagonists that increase the ER Ca2+ concentration leading to more Ca2+ binding by the chaperones, including calnexin and calreticulin, increasing their activity and ability to resculpt the folding free energy diagram of mutant lysosomal enzymes by “pushing” more protein toward the native state at the expense of misfolding.

Figure 4

Figure 4. Competition between Protein Folding and Degradation is a Central Feature of Proteostasis Network Function

Depicted is an Hsp-70-40-nucleotide exchange proteostasis pathway that is intentionally generic (not organelle specific), illustrating how the competition between folding and degradation of a foldable protein is affected. As can be discerned from this representative pathway, the concentrations and activity of many components (many not shown) influence the ratio of folding to degradation for a particular client protein.

Similar articles

Cited by

References

    1. Balch WE, Morimoto RI, Dillin A, Kelly JW. Adapting proteostasis for disease intervention. Science. 2008;319:916–919. Review describing the proteostasis network, how deficiencies in proteostasis results in various human diseases, and the utility of proteostasis regulators to manipulate the concentration, conformation, quaternary structure, and/or location of the protein(s) to ameliorate these diseases. - PubMed
    1. Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE. Biological and Chemical Approaches to Diseases of Proteostasis Deficiency. Annu Rev Biochem. 2009;78:23.21–33. - PubMed
    1. Deuerling E, Bukau B. Chaperone-assisted folding of newly synthesized proteins in the cytosol. Crit Rev Biochem Mol Biol. 2004;39:261–277. - PubMed
    1. Tang YC, Chang HC, Chakraborty K, Hartl FU, Hayer-Hartl M. Essential role of the chaperonin folding compartment in vivo. EMBO J. 2008;27:1458–1468. - PMC - PubMed
    1. Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006;125:443–451. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources