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PLoS Biol. 2014 Nov 18;12(11):e1001998. doi: 10.1371/journal.pbio.1001998. eCollection 2014 Nov.

Modulation of the maladaptive stress response to manage diseases of protein folding.

Author information

1
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
2
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
3
Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
4
Proteostasis Therapeutics Inc., Cambridge, Massachusetts, United States of America.
5
Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America.
6
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, United States of America; The Institute for Childhood and Neglected Diseases, The Scripps Research Institute, La Jolla, California, United States of America.

Abstract

Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD), Niemann-Pick type C1 disease (NPC1), Alzheimer's disease (AD), and cystic fibrosis (CF). Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR) pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR), through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.

PMID:
25406061
PMCID:
PMC4236052
DOI:
10.1371/journal.pbio.1001998
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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