Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 09 2023
15 09 2023
Historique:
received:
16
12
2022
accepted:
21
08
2023
medline:
18
9
2023
pubmed:
16
9
2023
entrez:
15
9
2023
Statut:
epublish
Résumé
A repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we investigate single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem motor and frontal cortices from C9-ALS, C9-FTD, and control donors. C9-ALS donors present pervasive alterations of gene expression with concordant changes in chromatin accessibility and histone modifications. The greatest alterations occur in upper and deep layer excitatory neurons, as well as in astrocytes. In neurons, the changes imply an increase in proteostasis, metabolism, and protein expression pathways, alongside a decrease in neuronal function. In astrocytes, the alterations suggest activation and structural remodeling. Conversely, C9-FTD donors have fewer high-quality neuronal nuclei in the frontal cortex and numerous gene expression changes in glial cells. These findings highlight a context-dependent molecular disruption in C9-ALS and C9-FTD, indicating unique effects across cell types, brain regions, and diseases.
Identifiants
pubmed: 37714849
doi: 10.1038/s41467-023-41033-y
pii: 10.1038/s41467-023-41033-y
pmc: PMC10504300
doi:
Substances chimiques
C9orf72 Protein
0
C9orf72 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5714Subventions
Organisme : NIA NIH HHS
ID : R01 AG067151
Pays : United States
Informations de copyright
© 2023. Springer Nature Limited.
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