Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration
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DOI：
10.1038/s41467-020-15794-9
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发表时间：
2020-04-23
影响因子：
16.6
通讯作者：
Zylka, Mark J.
中科院分区：
文献类型：
--
作者：
Fragola, Giulia;Mabb, Angela M.;Zylka, Mark J.
拓扑异构酶1（Topoisomerase 1，TOP 1）在转录过程中减轻DNA中的扭转应力，并促进长（> 100 kb）基因的表达，其中许多基因对神经元功能很重要。为了评估Top1的损失如何影响体内神经元，我们有条件地删除（cKO）小鼠大脑皮层和海马中有丝分裂后兴奋性神经元中的Top1。Top1 cKO神经元正常发育，但随后显示长基因的偏向性转录下调、DNA损伤迹象、神经炎症、聚（ADP-核糖）聚合酶-1（PARP 1）活性增加、单细胞体细胞突变和最终变性。用烟酰胺核苷补充烟酰胺腺嘌呤二核苷酸（NAD（+））部分阻断了神经变性，并将Top1 cKO小鼠的寿命延长了30%。p53的减少也部分挽救了皮质神经元的损失。虽然神经变性得到了部分挽救，但行为衰退并没有得到阻止。这些数据表明，当TOP1功能被破坏时，减少神经元损失不足以限制行为下降。拓扑异构酶1（Topoisomerase 1，TOP 1）在转录过程中缓解DNA扭转应力，并促进长神经元基因的表达。在这里，我们表明，在兴奋性神经元中的Top1的缺失导致早发性神经变性，这是部分依赖于p53/PARP 1激活和NAD（+）耗尽。
Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD(+)) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted. Topoisomerase 1 (TOP1) relieves DNA torsional stress during transcription and facilitates the expression of long neuronal genes. Here we show that deletion of Top1 in excitatory neurons leads to early onset neurodegeneration that is partially dependent on p53/PARP1 activation and NAD(+) depletion.