小柯机器人

美国西奈山艾坎医学院Towfique Raj和Jack Humphrey共同合作，近期取得重要工作进展。他们纽约基因组中心Raj, Towfique研究小组取得一项新突破。他们揭示了肌萎缩性脊髓侧索硬化症脊髓整合转录组分析提示神经胶质激活并提示新的风险基因。该项研究成果发表在2022年12月8日出版的《自然—神经科学》上。

据介绍，肌萎缩侧索硬化症（ALS）是一种逐渐致命的神经退行性疾病，影响大脑和脊髓中的运动神经元。

研究人员通过RNA测序研究了154名ALS患者和49名对照患者的380份颈、胸和腰脊髓节段的死后样本的基因表达变化。他们观察到小胶质细胞和星形胶质细胞基因表达增加，同时少突胶质细胞基因的表达减少。通过在ALS样本中创建基因共表达网络，研究人员确定了几个与回顾性疾病持续时间负相关的激活小胶质细胞模块。他们绘制了分子数量性状基因座图谱，发现几个潜在的ALS风险基因座，这些基因座可能通过基因表达或剪接在脊髓中起作用，并为FNBP1、ACSL5、SH3RF1和NFASC分配了假定的细胞类型。

总之，研究人员概述了与C9orf72剪接相关的常见遗传变异如何充当众所周知的重复扩增的代理，并使用相同机制来提示ATXN3是一个假定风险基因。

 附：英文原文

Title: Integrative transcriptomic analysis of the amyotrophic lateral sclerosis spinal cord implicates glial activation and suggests new risk genes

Author: Humphrey, Jack, Venkatesh, Sanan, Hasan, Rahat, Herb, Jake T., de Paiva Lopes, Katia, Kkali, Fahri, Byrska-Bishop, Marta, Evani, Uday S., Narzisi, Giuseppe, Fagegaltier, Delphine, Sleegers, Kristel, Phatnani, Hemali, Knowles, David A., Fratta, Pietro, Raj, Towfique

Issue&Volume: 2022-12-08

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressively fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. In this study, we investigated gene expression changes in ALS via RNA sequencing in 380 postmortem samples from cervical, thoracic and lumbar spinal cord segments from 154 individuals with ALS and 49 control individuals. We observed an increase in microglia and astrocyte gene expression, accompanied by a decrease in oligodendrocyte gene expression. By creating a gene co-expression network in the ALS samples, we identified several activated microglia modules that negatively correlate with retrospective disease duration. We mapped molecular quantitative trait loci and found several potential ALS risk loci that may act through gene expression or splicing in the spinal cord and assign putative cell types for FNBP1, ACSL5, SH3RF1 and NFASC. Finally, we outline how common genetic variants associated with splicing of C9orf72 act as proxies for the well-known repeat expansion, and we use the same mechanism to suggest ATXN3 as a putative risk gene.

DOI: 10.1038/s41593-022-01205-3

Source: https://www.nature.com/articles/s41593-022-01205-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex