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
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.
Front Neurosci. 2024 Feb 26;18:1258996. doi: 10.3389/fnins.2024.1258996. eCollection 2024.
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, 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 co-expressed genes correlated with patterns of cortical thickness in symptomatic pathogenic HRE carriers ( = 19) compared to controls ( = 23). Lastly, we explored whether genes with significant imaging transcriptomic correlations (i.e., " imaging transcriptomic network") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways.
A total of 2,120 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 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.
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）和ALS - FTD最常见的遗传病因。鉴定出与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中的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、皮质下和小脑）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54个已知与ALS、FTD或ALS - FTD相关的基因。然后，我们进行成像转录组分析，以评估与有症状的C9orf72致病性HRE携带者（n = 19）相比，对照者（n = 23）中鉴定出的C9orf72共表达基因是否与皮质厚度模式相关。最后，我们探究了具有显著C9orf72成像转录组相关性的基因（即“C9orf72成像转录组网络”）是否在大脑中的特定细胞群体中富集，以及是否在特定的生物学和分子途径中富集。
共有2120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成像转录组网络在先前与ALS和FTD相关的细胞群体中差异表达，包括5b层细胞、脊髓和脑干中的胆碱能神经元以及纹状体的中等棘状神经元，并且在与蛋白质泛素化、自噬、细胞对DNA损伤的反应、内质网到高尔基体囊泡介导的运输等相关的生物学和分子途径中富集。
综合考虑，我们鉴定出了一个C9orf72相关基因网络，该网络可能影响ALS/FTD中选择性区域和细胞类型特异性易损性。
