Ghaffari Layla T, Trotti Davide, Haeusler Aaron R
Jefferson Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA 19107, USA.
iScience. 2023 May 24;26(6):106959. doi: 10.1016/j.isci.2023.106959. eCollection 2023 Jun 16.
The (GC) nucleotide repeat expansion (NRE) mutation in C9orf72 is the most common genetic cause of ALS and FTD. The biological functions of C9orf72 are becoming understood, but it is unclear if this gene is regulated in a neural-specific manner. Neuronal activity is a crucial modifier of biological processes in health and neurodegenerative disease contexts. Here, we show that prolonged membrane depolarization in healthy human iPSC-cortical neurons leads to a significant downregulation of a transcript variant 3 (V3) of C9orf72, with a concomitant increase in variant 2 (V2), which leads to total C9orf72 RNA transcript levels remaining unchanged. However, the same response is not observed in cortical neurons derived from patients with the C9-NRE mutation. These findings reveal the impact of depolarization on C9orf72 transcripts, and how this response diverges in C9-NRE-carriers, which may have important implications in the underlying unique clinical associations of C9-NRE transcripts and disease pathogenesis.
C9orf72基因中的（GC）核苷酸重复扩增（NRE）突变是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传病因。人们对C9orf72的生物学功能的认识正在不断深入，但尚不清楚该基因是否以神经特异性方式受到调控。神经元活动是健康和神经退行性疾病背景下生物过程的关键调节因子。在此，我们表明，健康人诱导多能干细胞来源的皮质神经元中长时间的膜去极化会导致C9orf72转录变体3（V3）显著下调，同时变体2（V2）增加，这导致C9orf72 RNA转录本总水平保持不变。然而，在携带C9-NRE突变的患者来源的皮质神经元中未观察到相同的反应。这些发现揭示了去极化对C9orf72转录本的影响，以及这种反应在C9-NRE携带者中如何不同，这可能对C9-NRE转录本潜在的独特临床关联和疾病发病机制具有重要意义。
