Divergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation

Junhao Li, Manoj K. Jaiswal, Jo-Fan Chien, Alexey Kozlenkov, Jinyoung Jung, Ping Zhou, Mahammad Gardashli, Luc J. Pregent, Erica Engelberg-Cook, Dennis W. Dickson, Veronique V. Belzil, Eran A. Mukamel () and Stella Dracheva ()
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Junhao Li: University of California San Diego
Manoj K. Jaiswal: Icahn School of Medicine at Mount Sinai
Jo-Fan Chien: University of California San Diego
Alexey Kozlenkov: Icahn School of Medicine at Mount Sinai
Jinyoung Jung: Icahn School of Medicine at Mount Sinai
Ping Zhou: Icahn School of Medicine at Mount Sinai
Mahammad Gardashli: Mayo Clinic
Luc J. Pregent: Mayo Clinic
Erica Engelberg-Cook: Mayo Clinic
Dennis W. Dickson: Mayo Clinic
Veronique V. Belzil: Mayo Clinic
Eran A. Mukamel: University of California San Diego
Stella Dracheva: Icahn School of Medicine at Mount Sinai

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41033-y

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