Reducing TDP-43 aggregation does not prevent its cytotoxicity.
Reducing TDP-43 aggregation does not prevent its cytotoxicity.
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DOI：
10.1186/2051-5960-1-49
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发表时间：
2013-08-09
影响因子：
7.1
通讯作者：
Cynader MS
中科院分区：
文献类型：
--
作者：
Liu R;Yang G;Nonaka T;Arai T;Jia W;Cynader MS
TAR dna结合蛋白43 （TDP-43）是一种参与肌萎缩性侧索硬化症（ALS）和额颞叶变性（FTLD）病理的蛋白。在这些神经退行性疾病的患者中，TDP-43不会保持在其正常的核位置，而是在受病神经元的核和细胞质中形成不溶性聚集体。我们使用高密度肽阵列分析来确定TDP-43中与TDP-43自身结合的区域，并设计可能能够减少TDP-43聚集的候选肽。我们发现，用这种方法鉴定的两种合成肽可以有效地抑制HeLa细胞中TDP-43蛋白聚集体的形成，以浓度依赖的方式，其中突变的人类TDP-43基因过表达。然而，尽管减少聚集，这些肽不能减少或防止细胞死亡。在亚砷酸盐处理的HeLa细胞中也观察到类似的结果。我们再次发现野生型TDP-43的聚集减少，但细胞死亡没有差异。我们的研究结果表明，TDP-43聚集与细胞死亡过程有关，而不是直接原因。
TAR DNA-binding protein 43 (TDP-43) is a protein that is involved in the pathology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). In patients with these neurodegenerative diseases, TDP-43 does not remain in its normal nuclear location, but instead forms insoluble aggregates in both the nucleus and cytoplasm of affected neurons. We used high density peptide array analysis to identify regions in TDP-43 that are bound by TDP-43 itself and designed candidate peptides that might be able to reduce TDP-43 aggregation. We found that two of the synthetic peptides identified with this approach could effectively inhibit the formation of TDP-43 protein aggregates in a concentration-dependent manner in HeLa cells in which a mutated human TDP-43 gene was overexpressed. However, despite reducing aggregation, these peptides did not reduce or prevent cell death. Similar results were observed in HeLa cells treated with arsenite. Again we found reduced aggregation, in this case of wild type TDP-43, but no difference in cell death. Our results suggest that TDP-43 aggregation is associated with the cell death process rather than being a direct cause.
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通讯作者：
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