Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease
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 physio
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Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease Tessa Sinnige, Anan Yu, and Richard I. Morimoto
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 T. Sinnige · A. Yu · R. I. Morimoto (*) Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA e-mail: [email protected]
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
Protein misfolding · Molecular chaperones · Neurodegenerative diseases · Proteostasis
4.1
Introduction
Protein homeostasis is regulated by the proteostasis network (PN) to control protein synthesis, folding and macromolecular assembly, localization, and degradation, processes that are essential for all living cells and organisms. An imbalance in the PN enhances the properties of destabilized mutant proteins that take advantage of the capacity of molecular chaperones to escape unfolding and degradation, leading to malignant phenotypes in cancer (see other chapters in this collection). The opposite scenario of failure of protein homeostasis is associated with aging and a plethora of
© Springer Nature Switzerland AG 2020 M. L. Mendillo et al. (eds.), HSF1 and Molecular Chaperones in Biology and Cancer, Advances in Experimental Medicine and Biology 1243, https://doi.org/10.1007/978-3-030-40204-4_4
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protein misfolding diseases including Alzheimer’s substrate binding and release driven by ATP disease (AD), Parkinson’s disease (PD), hydrolysis. Hsp70 and its constitutively expressed Huntington’s disease (HD) and amyotrophic
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