Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.
Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.
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人工 microRNA 可抑制 C9ORF72 变异并减少体内有毒二肽重复蛋白。
DOI：
10.1038/s41434-023-00418-w
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发表时间：
2024
期刊：
影响因子：
5.1
通讯作者：
Mueller
中科院分区：
文献类型：
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作者：
Cabrera,GabrielaToro;Meijboom,KatharinaE;Abdallah,Abbas;Tran,Helene;Foster,Zachariah;Weiss,Alexandra;Wightman,Nicholas;Stock,Rachel;Gendron,Tania;Gruntman,Alisha;Giampetruzzi,Anthony;Petrucelli,Leonard;BrownJr,RobertH;Mueller
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，影响运动神经元，导致进行性肌无力和呼吸衰竭。在9号染色体开放阅读框72（C9 ORF72）中存在扩展的六核苷酸重复是引起家族性ALS和额颞叶痴呆（FTD）的最常见突变。为了确定抑制C9ORF72基因产物的表达是否可以降低毒性，我们设计了一组靶向人类C9ORF72基因的人工microRNA（amiRNA）。在这里，我们报告了AAV9介导的amiRNA显著抑制C9ORF72转基因小鼠脑和脊髓中C9ORF72 mRNA、蛋白和由扩增重复序列产生的毒性二肽重复序列蛋白的表达。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression ofC9ORF72gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the humanC9ORF72gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.