{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:59:34Z","timestamp":1768507174757,"version":"3.49.0"},"posted":{"date-parts":[[2023,7,19]]},"group-title":"Neuroscience","reference-count":65,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>\n                    A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (\n                    <jats:italic>C9orf72<\/jats:italic>\n                    ) 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\n                    <jats:italic>C9orf72<\/jats:italic>\n                    may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate\n                    <jats:italic>C9orf72<\/jats:italic>\n                    co-expression patterns. To do this, we correlated average\n                    <jats:italic>C9orf72<\/jats:italic>\n                    expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified\n                    <jats:italic>C9orf72<\/jats:italic>\n                    co-expressed genes correlated with patterns of cortical thickness in symptomatic\n                    <jats:italic>C9orf72<\/jats:italic>\n                    pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant\n                    <jats:italic>C9orf72<\/jats:italic>\n                    radiogenomic correlations (i.e., \u2018\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene network\u2019) were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to\n                    <jats:italic>C9orf72<\/jats:italic>\n                    and significantly correlated with patterns of cortical thickness in\n                    <jats:italic>C9orf72<\/jats:italic>\n                    HRE carriers. This\n                    <jats:italic>C9orf72<\/jats:italic>\n                    gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Considered together, we identified a network of\n                    <jats:italic>C9orf72<\/jats:italic>\n                    -associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS\/FTD.\n                  <\/jats:p>\n                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