iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons.
ALS
CP: Neuroscience
CP: Stem cell research
TDP-43
cell-type specificity
disease modeling
nonsense-mediated decay
splicing
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 09 2023
26 09 2023
Historique:
received:
27
09
2022
revised:
10
05
2023
accepted:
11
08
2023
medline:
5
10
2023
pubmed:
31
8
2023
entrez:
31
8
2023
Statut:
ppublish
Résumé
Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.
Identifiants
pubmed: 37651231
pii: S2211-1247(23)01057-4
doi: 10.1016/j.celrep.2023.113046
pmc: PMC10622181
mid: NIHMS1933889
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
113046Subventions
Organisme : NINDS NIH HHS
ID : RF1 NS127407
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS124203
Pays : United States
Organisme : NINDS NIH HHS
ID : DP2 NS106664
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS112503
Pays : United States
Organisme : NINDS NIH HHS
ID : F32 NS114319
Pays : United States
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests B.J.W. is a consultant and member of the scientific advisory board of Quralis and is a coinventor on patent US9517223B2, issued for use of potassium channel openers in neurodegenerative diseases.
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