Broce Iris J, Sirkis Daniel W, Nillo Ryan M, Bonham Luke W, Lee Suzee E, Miller Bruce, Castruita Patricia, Sturm Virginia E, Sugrue Leo S, Desikan Rahul S, Yokoyama Jennifer S
Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States.
Department of Neurosciences, University of California, San Diego, San Diego, CA, United States.
bioRxiv. 2023 Aug 3:2023.07.17.549377. doi: 10.1101/2023.07.17.549377.
A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 () 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 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis.
We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate co-expression patterns. To do this, we correlated average 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 co-expressed genes correlated with patterns of cortical thickness in symptomatic pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant radiogenomic correlations (i.e., ' gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.
A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to and significantly correlated with patterns of cortical thickness in HRE carriers. This 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.
Considered together, we identified a network of -associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.
9号染色体开放阅读框72（C9orf72）内含子中的六核苷酸重复扩增（HRE）被认为是肌萎缩侧索硬化症（ALS）、额颞叶痴呆（FTD）以及ALS-FTD最常见的遗传病因。识别与C9orf72具有相似区域共表达模式的基因，可能有助于识别介导ALS和FTD发病机制中选择性易损性的新基因靶点和生物学机制。
我们利用来自艾伦人类大脑图谱的健康大脑mRNA表达数据来评估C9orf72的共表达模式。为此，我们将不同解剖分区（皮质、皮质下、小脑）的51个区域中的平均C9orf72表达值与15633个蛋白质编码基因的平均基因表达值进行关联，其中包括50个已知与ALS、FTD或ALS-FTD相关的基因。然后，我们评估所识别出的与C9orf72共表达的基因是否与有症状的C9orf72致病性HRE携带者（n = 19）的皮质厚度模式相关。最后，我们探究具有显著C9orf72放射基因组相关性的基因（即“C9orf72基因网络”）是否在大脑中的特定细胞群体中富集，以及是否富含特定的生物学和分子途径。
共有1748个基因在大脑中的基因表达解剖分布与C9orf72相似，并且与C9orf72 HRE携带者的皮质厚度模式显著相关。这个C9orf72基因网络在先前与ALS和FTD相关的细胞群体中差异表达，包括5b层细胞、脊髓中的胆碱能运动神经元以及纹状体的中等棘状神经元，并且富含与多种神经递质系统、蛋白质泛素化、自噬和MAPK信号传导等相关的生物学和分子途径。
综合考虑，我们识别出了一个与C9orf72相关的基因网络，该网络可能影响ALS/FTD中选择性区域和细胞类型特异性的易损性。
