Single nucleus multiome analysis of the prefrontal cortex fromC9orf72ALS/FTD patients illuminates pathways affected during disease progression

Author:

Wang Hsiao-Lin V.ORCID,Veire Austin M.ORCID,Gendron Tania F.ORCID,Gearing MarlaORCID,Glass Jonathan D.ORCID,Jin PengORCID,Corces Victor G.ORCID,McEachin Zachary T.ORCID

Abstract

AbstractRepeat expansions in theC9orf72gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients withC9orf72ALS/FTD, we compared healthy controls withC9orf72ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during disease progression. These alterations include downregulation of nuclear and mitochondrial ribosomal protein genes in early disease stages that become upregulated as the disease progresses. High ratios of premature oligodendrocytes expressing low levels of genes encoding major myelin protein components are characteristic of late disease stages and may represent a unique signature ofC9orf72ALS/FTD. Microglia with increased reactivity and astrocyte specific transcriptome changes in genes involved in glucose/glycogen metabolism are also associated with disease progression. Late stages ofC9orf72ALS/FTD correlate with sequential changes in the regulatory landscape of several genes in glial cells, namelyMBP/MAG/MOGin oligodendrocytes,CD83/IRF8in microglia, andGLUT1/GYS2/AGLin astrocytes. Only layer 2-3 cortical projection neurons with high expression ofCUX2/LAMP5are significantly reduced inC9orf72ALS/FTD patients with respect to controls. Our findings reveal previously unknown progressive functional changes in cortical cells ofC9orf72ALS/FTD patients that shed light on the mechanisms underlying the pathology of this disease.

Publisher

Cold Spring Harbor Laboratory

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