A number of mutations in a gene encoding RNA-binding protein FUS have been linked to the development of a familial form of amyotrophic lateral sclerosis known as FUS-ALS. C-terminal truncations of FUS by either nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients bearing these highly pathogenic mutations the function of motor neurons is not noticeably compromised for at least a couple of decades, suggesting that until cytoplasmic levels of FUS lacking its C-terminal nuclear localisation signal reaches a critical threshold, motor neurons are able to tolerate its permanent production. In order to identify how the nervous system responds to low levels of pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1-359], with a low neuronal expression level of a highly aggregation-prone and pathogenic form of C-terminally truncated FUS. In contrast to mice that express substantially higher level of the same FUS variant and develop severe early onset motor neuron pathology, L-FUS[1-359] mice do not develop any clinical or histopathological signs of motor neuron deficiency even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice compared to their wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating for the potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective targets for therapy of FUS-ALS and possibly, other forms of ALS.

中文翻译：

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C端截短的人类FUS的低水平表达会导致无症状转基因小鼠的脊髓转录组发生广泛变化。

编码RNA结合蛋白FUS的基因中的许多突变都与家族性肌萎缩性侧索硬化症（称为FUS-ALS）的发展有关。通过无义或移码突变将FUS的C端截短导致FUS-ALS的发展，其起效特别快，且进展迅速。然而，即使在具有这些高致病性突变的患者中，运动神经元的功能也至少在几十年内并未受到明显损害，这表明直到缺乏其C端核定位信号的FUS的胞质水平达到临界阈值，运动神经元才被能够忍受其永久性生产。为了确定神经系统如何响应低水平的FUS致病变体，我们生产并鉴定了小鼠系L-FUS [1-359]，C末端截短的FUS具有高度聚集和致病形式的低神经元表达水平。与表达较高水平的相同FUS变体并发展出严重的早期发作运动神经元病理的小鼠相反，L-FUS [1-359]小鼠即使在老年时也没有任何运动神经元缺乏的临床或组织病理学迹象。然而，与野生型同窝仔相比，我们检测到这些小鼠的脊髓转录组发生了实质性变化。我们建议这些变化中的至少一些反映了细胞机制的激活，以补偿致病性FUS产生的潜在破坏作用。对这些机制的进一步研究可能揭示出治疗FUS-ALS以及可能的其他形式ALS的有效靶标。