C9ORF72 重复扩展改变神经发育。
The C9ORF72 repeat expansion alters neurodevelopment.
机构信息
Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of Southern California, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
出版信息
Cell Rep. 2023 Aug 29;42(8):112983. doi: 10.1016/j.celrep.2023.112983. Epub 2023 Aug 16.
Genetic mutations that cause adult-onset neurodegenerative diseases are often expressed during embryonic stages, but it is unclear whether they alter neurodevelopment and how this might influence disease onset. Here, we show that the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a repeat expansion in C9ORF72, restricts neural stem cell proliferation and reduces cortical and thalamic size in utero. Surprisingly, a repeat expansion-derived dipeptide repeat protein (DPR) not known to reduce neuronal viability plays a key role in impairing neurodevelopment. Pharmacologically mimicking the effects of the repeat expansion on neurodevelopment increases susceptibility of C9ORF72 mice to motor defects. Thus, the C9ORF72 repeat expansion stunts development of the brain regions prominently affected in C9ORF72 FTD/ALS patients.
导致成人发病的神经退行性疾病的基因突变通常在胚胎期表达，但尚不清楚它们是否会改变神经发育，以及这会如何影响疾病的发作。在这里，我们表明，最常见的额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的病因，即 C9ORF72 中的重复扩展，会限制神经干细胞的增殖并减少子宫内皮质和丘脑的大小。令人惊讶的是，一种重复扩展衍生的二肽重复蛋白（DPR），已知不会降低神经元活力，在损害神经发育方面却起着关键作用。药理学模拟重复扩展对神经发育的影响会增加 C9ORF72 小鼠对运动缺陷的易感性。因此，C9ORF72 重复扩展会阻碍 C9ORF72 FTD/ALS 患者受影响的大脑区域的发育。
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