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丧失TDP-43的功能有助于基因组不稳定性在肌缩性侧面硬化症

Minggang Fang¹, Sara K Deibler¹, Alissa L Nana²

¹Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, United States.

Frontiers in neuroscience

|October 18, 2023

概括

在肌缩侧硬化 (ALS) 和前性痴呆 (FTD) 中,核TDP-43功能丧失会提高DNA突变率和基因组不稳定性. 这种DNA损伤损害了修复途径,减少了神经元的存活率,突出了这些神经退行性疾病的关键病理特征.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
分子生物学分子生物学

背景情况:

细胞质中TDP-43的错位是ALS和FTD的标志.
核TDP-43损失在疾病发病过程中的作用尚不清楚.

研究的目的:

调查TDP-43功能丧失在ALS和FTD中的功能后果.
为了确定基因组不稳定是否是TDP-43蛋白质病变的特征.

主要方法:

大规模的RNAi查,以确定影响DNA突变率的基因.
诱导多能干细胞 (iPSC) 和来自ALS患者的衍生神经元的分析.
对DNA双链断裂修复通路 (NHEJ和HR) 的评估.
在诱导DNA损伤后评估神经元存活率.

主要成果:

TARDBP (编码为TDP-43) 的功能丧失会增加DNA突变率和基因组不稳定性.
来自ALS患者的iPSC神经元由于NHEJ和HR受损而导致DNA损伤增加.
来自ALS iPSC的神经元在暴露于破坏DNA的物质后的存活率降低.
在患者脑组织中核 TDP-43 枯竭的神经元中观察到较高的 DNA 损伤.

结论:

核TDP-43功能丧失导致ALS/FTD的基因组不稳定性和DNA损伤.
损坏的DNA修复机制有助于TDP-43蛋白质病变中的神经退行.
基因组不稳定性是TDP-43病理的ALS/FTD患者的关键病理特征.

关键词:

修复DNA的修复DNA的修复在TDP-43中使用.骨髓缩侧面硬化症 (ALS) 是一种前性痴呆症前性痴呆症基因组的不稳定性同类的重组组合.

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