A hexanucleotide repeat expansion at C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Initial studies of bacterial artificial chromosome (BAC) transgenic mice harboring this expansion described an absence of motor and survival phenotypes. However, a recent study by Liu and colleagues described transgenic mice harboring a large repeat expansion (C9-500) and reported decreased survival and progressive motor phenotypes. To determine the utility of the C9-500 animals for understanding degenerative mechanisms, we validated and established two independent colonies of transgene carriers. However, extended studies of these animals for up to 1 year revealed no reproducible abnormalities in survival, motor function, or neurodegeneration. Here, we propose several potential explanations for the disparate nature of our findings from those of Liu and colleagues. Resolving the discrepancies we identify will be essential to settle the translational utility of C9-500 mice. This Matters Arising paper is in response to Liu et al. (2016), published in Neuron. See also the response by Nguyen et al. (2020), published in this issue.

C9ORF72处的六核苷酸重复扩增是肌萎缩性侧索硬化症（ALS）/额颞痴呆（FTD）的最常见遗传原因。细菌人工染色体（BAC）转基因小鼠具有这种扩展的初步研究描述了缺乏运动和生存表型。但是，Liu及其同事的最新研究描述了具有较大重复扩增（C9-500）的转基因小鼠，并报道了存活率降低和进行性运动表型降低。为了确定C9-500动物了解退化机制的效用，我们验证并建立了两个独立的转基因载体集落。但是，对这些动物进行的长达1年的扩展研究表明，它们在生存，运动功能或神经变性方面没有可再现的异常。这里，对于我们的研究结果与刘及其同事的研究结果截然不同，我们提出了几种可能的解释。解决我们发现的差异对于解决C9-500小鼠的翻译实用性至关重要。该问题发表论文是对Liu等人的回应。（2016），发表于神经元。另请参见Nguyen等的回应。（2020年），本期出版。