title: Modulation of the maladaptive stress response to manage diseases of protein folding.
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.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Daniela Martino
authors.initials: DM
authors.lastname: Roth
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Jiansong
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Bouchecareilh
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Theo
authors.initials: T
authors.lastname: Seeley
authors.affiliation: 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.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: 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.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
authors.affiliation: Proteostasis Therapeutics Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Garza
authors.affiliation: Proteostasis Therapeutics Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Drew
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
authors.affiliation: 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.
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D017173:Caenorhabditis elegans; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004224:Diterpenes / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004852:Epoxy Compounds / Q000627:therapeutic use; D020868:Gene Silencing; D000076249:Heat Shock Transcription Factors; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D009940:Organoids; D010616:Phenanthrenes / Q000627:therapeutic use; D000071876:Prostaglandin-E Synthases; D017510:Protein Folding; D057165:Proteostasis Deficiencies / Q000235:genetics*; D020545:Respiratory Mucosa / Q000378:metabolism; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; C505032:CFTR protein, human; D004268:DNA-Binding Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D010616:Phenanthrenes; D014157:Transcription Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C001899:triptolide; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases