Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, 32224, USA.
Nat Commun. 2019 Nov 29;10(1):5466. doi: 10.1038/s41467-019-13477-8.
Expanded GGGGCC (GC) repeats in C9ORF72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How RNAs containing expanded GC repeats are transcribed in human neurons is largely unknown. Here we describe a Drosophila model in which poly(GR) expression in adult neurons causes axonal and locomotor defects and premature death without apparent TDP-43 pathology. In an unbiased genetic screen, partial loss of Lilliputian (Lilli) activity strongly suppresses poly(GR) toxicity by specifically downregulating the transcription of GC-rich sequences in Drosophila. Knockout of AFF2/FMR2 (one of four mammalian homologues of Lilli) with CRISPR-Cas9 decreases the expression of the mutant C9ORF72 allele containing expanded GC repeats and the levels of repeat RNA foci and dipeptide repeat proteins in cortical neurons derived from induced pluripotent stem cells of C9ORF72 patients, resulting in rescue of axonal degeneration and TDP-43 pathology. Thus, AFF2/FMR2 regulates the transcription and toxicity of expanded GC repeats in human C9ORF72-ALS/FTD neurons.
GGGCC（GC）重复序列扩增导致 C9ORF72 肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）。目前尚不清楚人类神经元中含有扩增 GC 重复序列的 RNA 是如何转录的。在这里，我们描述了一个果蝇模型，其中成年神经元中聚（GR）的表达导致轴突和运动缺陷以及过早死亡，而没有明显的 TDP-43 病理学。在一项无偏遗传筛选中，Lilliputian（Lilli）活性的部分缺失通过特异性下调果蝇中富含 GC 的序列的转录强烈抑制聚（GR）毒性。CRISPR-Cas9 敲除 AFF2/FMR2（Lilli 的四个哺乳动物同源物之一）可降低含有扩增 GC 重复的突变 C9ORF72 等位基因的表达以及重复 RNA 焦点和二肽重复蛋白的水平源自 C9ORF72 患者诱导多能干细胞的皮质神经元，导致轴突退化和 TDP-43 病理学的挽救。因此，AFF2/FMR2 调节人类 C9ORF72-ALS/FTD 神经元中扩增 GC 重复的转录和毒性。
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