DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity.
DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity.
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DOI：
10.1007/s00018-021-03872-0
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Ferraiuolo L
中科院分区：
文献类型：
--
作者：
Kok JR;Palminha NM;Dos Santos Souza C;El-Khamisy SF;Ferraiuolo L
越来越多的证据支持DNA损伤参与多种神经退行性疾病，包括肌萎缩侧索硬化症（ALS）。在散发性和家族性肌萎缩侧索硬化症中都观察到DNA损伤水平升高，这也可能在西太平洋肌萎缩侧索硬化症中发挥作用，这被认为是由环境原因引起的。肌萎缩侧索硬化症DNA损伤的原因尚不清楚，但可能在不同的遗传亚群之间有所不同。C9ORF72基因的重复扩增是家族性ALS最常见的遗传原因，约占散发病例的10%。已知这些基因突变会引起r环，从而增加基因组的不稳定性和DNA损伤，并产生二肽重复蛋白，这已被证明会导致DNA损伤和DNA损伤反应的损害。同样，一些与ALS相关的基因，包括TARDBP、FUS、NEK1、SQSTM1和SETX，已知在DNA修复和DNA损伤反应中发挥作用，因此可能通过这些途径促进神经元死亡。散发性和家族性ALS的另一个一致特征是星形胶质细胞诱导运动神经元死亡的能力，尽管引起这种毒性的因素在很大程度上仍然未知。在这篇综述中，我们总结了DNA损伤在ALS发病机制中起病因或继发性作用的证据，并讨论了不同遗传亚型所涉及的可能机制，特别关注星形胶质细胞在神经元中启动或延续DNA损伤的作用。
Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.
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