Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations
Primary fibroblasts cultures reveal TDP-43 abnormalities in amyotrophic lateral sclerosis patients with and without SOD1 mutations
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DOI：
10.1016/j.neurobiolaging.2015.02.009
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发表时间：
2015-05-01
影响因子：
4.2
通讯作者：
Moncada, Alice
中科院分区：
文献类型：
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作者：
Sabatelli, Mario;Zollino, Marcella;Moncada, Alice
TAR DNA结合蛋白43（TDP-43）是肌萎缩侧索硬化（ALS）患者运动神经元中观察到的病理性包涵体的主要成分。我们检测了22名ALS患者的原代成纤维细胞培养物中TDP-43的表达，包括SOD 1（n = 4），TARDBP（n = 4），FUS（n = 2）和C9 ORF 72（n = 3）突变的病例和9名无遗传缺陷的患者。通过使用磷酸化非依赖性抗体，15例患者显示细胞核或细胞质隔室中TDP-43水平的显著改变。特别地，在所有具有C9 ORF 72和TARDBP突变的病例、1名具有FUS突变的患者和3名没有遗传缺陷的患者的细胞质中观察到TDP-43的显著积聚。SOD 1突变的患者显示TDP-43在细胞核中显著减少，而无细胞质错误定位。这些变化与存在截短和磷酸化的TDP-43物质有关。我们的研究结果表明，成纤维细胞概括了在神经元细胞中观察到的一些标志性TDP-43异常。突变型SOD 1细胞中全长TDP-43水平的降低表明至少一些SOD 1突变改变TDP-43代谢。(C)2015爱思唯尔公司All rights reserved.
TAR DNA-binding protein 43 (TDP-43) is a major component of the pathologic inclusions observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients. We examined TDP-43 expression in primary fibroblasts cultures from 22 ALS patients, including cases with SOD1 (n = 4), TARDBP (n = 4), FUS (n = 2), and C9ORF72 (n = 3) mutations and 9 patients without genetic defect. By using a phosphorylation-independent antibody, 15 patients showed notable alterations of TDP-43 level in the nuclear or cytoplasmic compartments. In particular, a marked accumulation of TDP-43 was observed in the cytoplasm of all cases with C9ORF72 and TARDBP mutations, 1 patient with FUS mutation and 3 patients without genetic defect. Patients with SOD1 mutations revealed a significant reduction of TDP-43 in the nuclei without cytoplasmic mislocalization. These changes were associated with the presence of truncated and phosphorylated TDP-43 species. Our results show that fibroblasts recapitulate some of hallmark TDP-43 abnormalities observed in neuronal cells. The reduction of full-length TDP-43 level in mutant SOD1 cells indicates that at least some SOD1 mutations alter TDP-43 metabolism. (C) 2015 Elsevier Inc. All rights reserved.