PMID- 25406061
OWN - NLM
STAT- MEDLINE
DCOM- 20151221
LR  - 20201217
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 12
IP  - 11
DP  - 2014 Nov
TI  - Modulation of the maladaptive stress response to manage diseases of protein 
      folding.
PG  - e1001998
LID - 10.1371/journal.pbio.1001998 [doi]
LID - e1001998
AB  - 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.
FAU - Roth, Daniela Martino
AU  - Roth DM
AD  - Department of Cell Biology, The Scripps Research Institute, La Jolla, California, 
      United States of America.
FAU - Hutt, Darren M
AU  - Hutt DM
AD  - Department of Cell Biology, The Scripps Research Institute, La Jolla, California, 
      United States of America.
FAU - Tong, Jiansong
AU  - Tong J
AD  - Department of Cell Biology, The Scripps Research Institute, La Jolla, California, 
      United States of America.
FAU - Bouchecareilh, Marion
AU  - Bouchecareilh M
AD  - Department of Cell Biology, The Scripps Research Institute, La Jolla, California, 
      United States of America.
FAU - Wang, Ning
AU  - Wang N
AD  - Department of Molecular Biosciences, Rice Institute for Biomedical Research, 
      Northwestern University, Evanston, Illinois, United States of America.
FAU - Seeley, Theo
AU  - Seeley T
AD  - Department of Cell Biology, The Scripps Research Institute, La Jolla, California, 
      United States of America.
FAU - Dekkers, Johanna F
AU  - Dekkers JF
AD  - 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.
FAU - Beekman, Jeffrey M
AU  - Beekman JM
AD  - 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.
FAU - Garza, Dan
AU  - Garza D
AD  - Proteostasis Therapeutics Inc., Cambridge, Massachusetts, United States of 
      America.
FAU - Drew, Lawrence
AU  - Drew L
AD  - Proteostasis Therapeutics Inc., Cambridge, Massachusetts, United States of 
      America.
FAU - Masliah, Eliezer
AU  - Masliah E
AD  - Department of Neurosciences, University of California, San Diego, La Jolla, 
      California, United States of America.
FAU - Morimoto, Richard I
AU  - Morimoto RI
AD  - Department of Molecular Biosciences, Rice Institute for Biomedical Research, 
      Northwestern University, Evanston, Illinois, United States of America.
FAU - Balch, William E
AU  - Balch WE
AD  - 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.
LA  - eng
GR  - HL079442/HL/NHLBI NIH HHS/United States
GR  - DK785483/DK/NIDDK NIH HHS/United States
GR  - GM42336/GM/NIGMS NIH HHS/United States
GR  - R01 GM038109/GM/NIGMS NIH HHS/United States
GR  - P01 AG031097/AG/NIA NIH HHS/United States
GR  - AG026647/AG/NIA NIH HHS/United States
GR  - R37 AG018440/AG/NIA NIH HHS/United States
GR  - R01 HL095524/HL/NHLBI NIH HHS/United States
GR  - R01 AG026647/AG/NIA NIH HHS/United States
GR  - AG5131/AG/NIA NIH HHS/United States
GR  - R37 GM038109/GM/NIGMS NIH HHS/United States
GR  - P50 AG005131/AG/NIA NIH HHS/United States
GR  - 5P01AG031097/AG/NIA NIH HHS/United States
GR  - R37 AG026647/AG/NIA NIH HHS/United States
GR  - GM81192/GM/NIGMS NIH HHS/United States
GR  - R01 GM042336/GM/NIGMS NIH HHS/United States
GR  - P30 NS076411/NS/NINDS NIH HHS/United States
GR  - MRC_/Medical Research Council/United Kingdom
GR  - GM38109/GM/NIGMS NIH HHS/United States
GR  - R01 GM033301/GM/NIGMS NIH HHS/United States
GR  - CAPMC/CIHR/Canada
GR  - R01 AG018440/AG/NIA NIH HHS/United States
GR  - AG18440/AG/NIA NIH HHS/United States
GR  - R01 HL079442/HL/NHLBI NIH HHS/United States
GR  - GM33301/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20141118
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (CFTR protein, human)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Diterpenes)
RN  - 0 (Epoxy Compounds)
RN  - 0 (HSF1 protein, human)
RN  - 0 (Heat Shock Transcription Factors)
RN  - 0 (Phenanthrenes)
RN  - 0 (Transcription Factors)
RN  - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator)
RN  - 19ALD1S53J (triptolide)
RN  - EC 5.3.- (Intramolecular Oxidoreductases)
RN  - EC 5.3.99.3 (Prostaglandin-E Synthases)
SB  - IM
CIN - PLoS Biol. 2014 Nov;12(11):e1001999. PMID: 25405339
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/therapeutic use
MH  - Caenorhabditis elegans
MH  - Cell Line
MH  - Cystic Fibrosis/drug therapy/*etiology/metabolism
MH  - Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism
MH  - DNA-Binding Proteins/*genetics/metabolism
MH  - Diterpenes/therapeutic use
MH  - Drug Evaluation, Preclinical
MH  - Epoxy Compounds/therapeutic use
MH  - Gene Silencing
MH  - Heat Shock Transcription Factors
MH  - Humans
MH  - Intramolecular Oxidoreductases/genetics/metabolism
MH  - Mice, Transgenic
MH  - Organoids
MH  - Phenanthrenes/therapeutic use
MH  - Prostaglandin-E Synthases
MH  - Protein Folding
MH  - Proteostasis Deficiencies/*genetics
MH  - Respiratory Mucosa/metabolism
MH  - Stress, Physiological
MH  - Transcription Factors/*genetics/metabolism
PMC - PMC4236052
COIS- The authors have declared that no competing interests exist.
EDAT- 2014/11/19 06:00
MHDA- 2015/12/22 06:00
PMCR- 2014/11/18
CRDT- 2014/11/19 06:00
PHST- 2014/03/31 00:00 [received]
PHST- 2014/10/07 00:00 [accepted]
PHST- 2014/11/19 06:00 [entrez]
PHST- 2014/11/19 06:00 [pubmed]
PHST- 2015/12/22 06:00 [medline]
PHST- 2014/11/18 00:00 [pmc-release]
AID - PBIOLOGY-D-14-01135 [pii]
AID - 10.1371/journal.pbio.1001998 [doi]
PST - epublish
SO  - PLoS Biol. 2014 Nov 18;12(11):e1001998. doi: 10.1371/journal.pbio.1001998. 
      eCollection 2014 Nov.