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

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HSF1 and Molecular Chaperones in Biology and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1243))

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.

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Acknowledgements

We thank Christopher M. Dobson for critical reading of part of the manuscript. This work was supported by National Institutes of Health (National Institute on Aging), the Daniel F. and Ada L. Rice Foundation to RIM and research grants from Eli Lilly & Co Ltd, Lilly Research Centre and the Tau Consortium of the Rainwater Foundation.

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  1. Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA

    Tessa Sinnige, Anan Yu & Richard I. Morimoto

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  1. Tessa Sinnige
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  2. Anan Yu
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Correspondence to Richard I. Morimoto .

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  1. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Marc Laurence Mendillo

  2. University of Chicago, Chicago, IL, USA

    David Pincus

  3. Weizmann Institute of Science, Rehovot, Israel

    Ruth Scherz-Shouval

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Sinnige, T., Yu, A., Morimoto, R.I. (2020). Challenging Proteostasis: Role of the Chaperone Network to Control Aggregation-Prone Proteins in Human Disease. In: Mendillo, M.L., Pincus, D., Scherz-Shouval, R. (eds) HSF1 and Molecular Chaperones in Biology and Cancer. Advances in Experimental Medicine and Biology, vol 1243. Springer, Cham. https://doi.org/10.1007/978-3-030-40204-4_4

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