外被体亚基 EXOC2 调节 C9ORF72-ALS/FTD 中扩展的 GGGGCC 重复序列的毒性。
The exocyst subunit EXOC2 regulates the toxicity of expanded GGGGCC repeats in C9ORF72-ALS/FTD.
机构信息
Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Graduate Program in Neuroscience, Morningside Graduate School of Biomedical Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Frontotemporal Dementia Research Center, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
出版信息
Cell Rep. 2024 Jul 23;43(7):114375. doi: 10.1016/j.celrep.2024.114375. Epub 2024 Jun 26.
GGGGCC (GC) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this genetic mutation leads to neurodegeneration remains largely unknown. Using CRISPR-Cas9 technology, we deleted EXOC2, which encodes an essential exocyst subunit, in induced pluripotent stem cells (iPSCs) derived from C9ORF72-ALS/FTD patients. These cells are viable owing to the presence of truncated EXOC2, suggesting that exocyst function is partially maintained. Several disease-relevant cellular phenotypes in C9ORF72 iPSC-derived motor neurons are rescued due to, surprisingly, the decreased levels of dipeptide repeat (DPR) proteins and expanded GC repeats-containing RNA. The treatment of fully differentiated C9ORF72 neurons with EXOC2 antisense oligonucleotides also decreases expanded GC repeats-containing RNA and partially rescued disease phenotypes. These results indicate that EXOC2 directly or indirectly regulates the level of GC repeats-containing RNA, making it a potential therapeutic target in C9ORF72-ALS/FTD.
GGGCC (GC) 重复扩展在 C9ORF72 中是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传原因。这种基因突变如何导致神经退行性变在很大程度上仍然未知。使用 CRISPR-Cas9 技术，我们在源自 C9ORF72-ALS/FTD 患者的诱导多能干细胞（iPSC）中删除了 EXOC2，该基因编码必需的外泌体亚基。这些细胞由于存在截断的 EXOC2 而具有活力，表明外泌体功能部分得到维持。由于令人惊讶的是二肽重复（DPR）蛋白和扩展的 GC 重复 RNA 的水平降低，源自 C9ORF72 的 iPSC 衍生运动神经元中的几种与疾病相关的细胞表型得到挽救。用 EXOC2 反义寡核苷酸完全分化的 C9ORF72 神经元的处理也降低了扩展的 GC 重复 RNA，并部分挽救了疾病表型。这些结果表明，EXOC2 直接或间接调节 GC 重复 RNA 的水平，使其成为 C9ORF72-ALS/FTD 的潜在治疗靶标。
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