AUTHOR=Broce Iris J. , Sirkis Daniel W. , Nillo Ryan M. , Bonham Luke W. , Lee Suzee E. , Miller Bruce L. , Castruita Patricia A. , Sturm Virginia E. , Sugrue Leo S. , Desikan Rahul S. , Yokoyama Jennifer S. 

TITLE=C9orf72 gene networks in the human brain correlate with cortical thickness in C9-FTD and implicate vulnerable cell types

JOURNAL=Frontiers in Neuroscience

VOLUME=18

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1258996

DOI=10.3389/fnins.2024.1258996

ISSN=1662-453X

ABSTRACT=<sec><title>Introduction</title><p>A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (<italic>C9orf72</italic>) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to <italic>C9orf72</italic> may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.</p></sec><sec><title>Methods</title><p>We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate <italic>C9orf72</italic> co-expression patterns. To do this, we correlated average <italic>C9orf72</italic> expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified <italic>C9orf72</italic> co-expressed genes correlated with patterns of cortical thickness in symptomatic <italic>C9orf72</italic> pathogenic HRE carriers (<italic>n</italic> = 19) compared to controls (<italic>n</italic> = 23). Lastly, we explored whether genes with significant <italic>C9orf72</italic> imaging transcriptomic correlations (i.e., “<italic>C9orf72</italic> imaging transcriptomic network”) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.</p></sec><sec><title>Results</title><p>A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to <italic>C9orf72</italic> and significantly correlated with patterns of cortical thickness in <italic>C9orf72</italic> HRE carriers. This <italic>C9orf72</italic> imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others.</p></sec><sec><title>Conclusion</title><p>Considered together, we identified a network of <italic>C9orf72</italic> associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.</p></sec>