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- Title
Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation.
- Authors
Li, Junhao; Jaiswal, Manoj K.; Chien, Jo-Fan; Kozlenkov, Alexey; Jung, Jinyoung; Zhou, Ping; Gardashli, Mahammad; Pregent, Luc J.; Engelberg-Cook, Erica; Dickson, Dennis W.; Belzil, Veronique V.; Mukamel, Eran A.; Dracheva, Stella
- Abstract
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. Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients' brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Subjects
GENETIC regulation; AMYOTROPHIC lateral sclerosis; NEUROGLIA; CELL analysis; FRONTAL lobe; SOMATIC cell nuclear transfer; POSTMORTEM changes
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41033-y