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首页> 外文期刊>Neuropathology and applied neurobiology >Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusions
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Transportin 1 colocalization with Fused in Sarcoma (FUS) inclusions is not characteristic for amyotrophic lateral sclerosis-FUS confirming disrupted nuclear import of mutant FUS and distinguishing it from frontotemporal lobar degeneration with FUS inclusions

机译：运输蛋白1与融合在肉瘤（FUS）夹杂物中的共定位不是肌萎缩性侧索硬化的特征-FUS证实了突变FUS的核输入受到破坏并与FUS夹杂物使额颞叶变性相区别

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Aims: Transportin 1 (TNPO 1) is an abundant component of the Fused in Sarcoma (FUS)-immunopositive inclusions seen in a subgroup of frontotemporal lobar degeneration (FTLD-FUS). TNPO 1 has been shown to bind to the C-terminal nuclear localizing signal (NLS) of FUS and mediate its nuclear import. Amyotrophic lateral sclerosis (ALS)-linked C-terminal mutants disrupt TNPO 1 binding to the NLS and impair nuclear import in cell culture. If this held true for human ALS then we predicted that FUS inclusions in patients with C-terminal FUS mutations would not colocalize with TNPO 1. Methods: Expression of TNPO 1 and colocalization with FUS was studied in the frontal cortex of FTLD-FUS (n=3) and brain and spinal cord of ALS-FUS (n=3), ALS-C9orf72 (n=3), sporadic ALS (n=7) and controls (n=7). Expression levels and detergent solubility of TNPO 1 was measured by Western blot. Results: Aggregates of TNPO 1 were abundant and colocalized with FUS inclusions in the cortex of all FTLD-FUS cases. In contrast, no TNPO 1-positive aggregates or FUS colocalization was evident in two-thirds, ALS-FUS cases and was rare in one ALS-FUS case. Nor were they present in C9orf72 or sporadic ALS. No increase in the levels of TNPO 1 was seen in Western blots of spinal cord tissues from all ALS cases compared with controls. Conclusions: These findings confirm that C-terminal FUS mutations prevent TNPO 1 binding to the NLS, inhibiting nuclear import and promoting cytoplasmic aggregation. The presence of TNPO 1 in wild-type FUS aggregates in FTLD-FUS distinguishes the two pathologies and implicates different disease mechanisms.
机译：目的：运输蛋白1（TNPO 1）是额颞叶变性（FTLD-FUS）亚组中可见的融合型肉瘤（FUS）-免疫阳性夹杂物的重要组成部分。 TNPO 1已显示与FUS的C端核定位信号（NLS）结合并介导其核输入。肌萎缩性侧索硬化症（ALS）连锁的C端突变体破坏TNPO 1与NLS的结合并损害细胞培养中的核输入。如果这对于人类ALS成立，那么我们预测C端FUS突变患者中的FUS夹杂物不会与TNPO 1共定位。方法：在FTLD-FUS的额皮质中研究了TNPO 1的表达和与FUS共定位（n = 3）以及ALS-FUS（n = 3），ALS-C9orf72（n = 3），散发性ALS（n = 7）和对照（n = 7）的脑和脊髓。通过蛋白质印迹法测量TNPO 1的表达水平和去污剂溶解度。结果：在所有FTLD-FUS病例的皮层中，TNPO 1聚集体丰富且与FUS夹杂物共定位。相反，在三分之二的ALS-FUS病例中没有TNPO 1阳性聚集体或FUS共定位，而在一个ALS-FUS病例中很少见。它们也不存在于C9orf72或散发性ALS中。与对照相比，在所有ALS病例的脊髓组织的Western印迹中均未发现TNPO 1的水平增加。结论：这些发现证实C末端FUS突变阻止TNPO 1与NLS结合，抑制核输入并促进细胞质聚集。 FTLD-FUS中野生型FUS聚集物中TNPO 1的存在区分了两种病理，并暗示了不同的疾病机制。

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