Expression of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling in an Induced Pluripotent Stem Cell Model of Systemic Amyloid Disease.
Activating Transcription Factor 6
/ metabolism
Amyloid
/ metabolism
Amyloid Neuropathies, Familial
/ genetics
Gene Editing
Gene Expression Regulation
Hepatocytes
/ metabolism
Humans
Induced Pluripotent Stem Cells
/ pathology
Liver
/ pathology
Models, Biological
Mutation
/ genetics
Prealbumin
/ genetics
Promoter Regions, Genetic
/ genetics
Protein Stability
Proteostasis
Sequence Analysis, RNA
Signal Transduction
Single-Cell Analysis
Stress, Physiological
Transferrin
/ metabolism
Unfolded Protein Response
amyloid
gene editing
hepatic disease
hereditary amyloidosis
pluripotent stem cells
protein folding disorders
proteostasis
single cell RNA sequencing
transthyretin
unfolded protein response
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
11 08 2020
11 08 2020
Historique:
received:
13
01
2020
revised:
01
07
2020
accepted:
02
07
2020
pubmed:
1
8
2020
medline:
3
6
2021
entrez:
1
8
2020
Statut:
ppublish
Résumé
The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of hepatocyte-like cells (HLCs) to the proteotoxicity of secreted transthyretin (TTR). To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We combined this tool with single-cell RNA sequencing to identify hepatic proteostasis factors correlating with destabilized TTR production in iPSC-derived HLCs. By generating an ATF6 inducible patient-specific iPSC line, we demonstrated that enhancing hepatic ER proteostasis preferentially reduces the secretion of amyloidogenic TTR. These data highlight the liver's capacity to chaperone misfolded TTR prior to deposition, and moreover suggest the potential for unfolded protein response modulating therapeutics in the treatment of diverse systemic amyloidoses.
Identifiants
pubmed: 32735824
pii: S2213-6711(20)30246-0
doi: 10.1016/j.stemcr.2020.07.003
pmc: PMC7419739
pii:
doi:
Substances chimiques
ATF6 protein, human
0
Activating Transcription Factor 6
0
Amyloid
0
Prealbumin
0
Transferrin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
515-528Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103533
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131697
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS092829
Pays : United States
Organisme : NIDDK NIH HHS
ID : F31 DK121481
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK102635
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001430
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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