Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.
Loss of Adaptive DNA Breaks in Alzheimer's Disease Brains.
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阿尔茨海默病大脑中适应性 DNA 断裂的丧失。
DOI：
10.1101/2023.12.11.566423
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Wang,Ning
中科院分区：
文献类型：
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作者：
Zhang,Xiaoyu;Haeri,Mohammad;Swerdlow,RussellH;Wang,Ning
背景：DNA断裂在阿尔茨海默病（AD）大脑中积累。虽然它们作为真正的基因组病变的作用是公认的，但DNA断裂也通过促进活动依赖性立即早期基因的表达来支持认知功能。这个过程涉及TOP 2B，一种催化DNA双链断裂形成的DNA拓扑异构酶。目的：研究AD如何影响神经系统基因的适应性DNA断裂。研究方法：我们利用DNA单链和双链断裂的能力来激活聚（ADP-核糖）聚合酶（PARP），该聚合酶将聚（ADP-核糖）（PAR）与相邻蛋白质缀合。为了表征AD脑中携带DNA断裂的基因组位点，通过CUT&RUN分析从3个AD和3个非痴呆尸检脑（额叶皮质，所有男性供体，年龄78至91岁）提取的细胞核，其中我们用随后的DNA测序靶向PAR。结果如下：虽然AD大脑中的PAR峰是非痴呆大脑的19.9倍，但AD大脑中神经系统基因的PAR峰严重丢失，这些基因的表达下调。这一结果与我们之前靶向H2 AX的CUT&RUN一致，H2 AX标记DNA双链断裂。此外，TOP 2B的表达显着下降，在AD brains.Conclusions：虽然AD大脑包含一个净增加的DNA断裂，适应性DNA断裂在神经系统基因在AD大脑丢失。这可能反映了TOP 2B表达的减少，并导致AD患者的神经元功能和认知受损。
Background: DNA breaks accumulate in Alzheimer’s disease (AD) brains. While their role as true genomic lesions is recognized, DNA breaks also support cognitive function by facilitating the expression of activity-dependent immediate early genes. This process involves TOP2B, a DNA topoisomerase that catalyzes the formation of DNA double-strand breaks. Objective: To characterize how AD impacts adaptive DNA breaks at nervous system genes. Methods: We leveraged the ability of DNA single-and double-strand breaks to activate poly (ADP-ribose) polymerases (PARPs) that conjugate poly (ADP-ribose)(PAR) to adjacent proteins. To characterize the genomic sites harboring DNA breaks in AD brains, nuclei extracted from 3 AD and 3 non-demented autopsy brains (frontal cortex, all male donors, age 78 to 91 years of age) were analyzed through CUT&RUN in which we targeted PAR with subsequent DNA sequencing. Results: Although the AD brains contained 19.9 times more PAR peaks than the non-demented brains, PAR peaks at nervous system genes were profoundly lost in AD brains, and the expression of these genes was downregulated. This result is consistent with our previous CUT&RUN targeting H2AX, which marks DNA double-strand breaks. In addition, TOP2B expression was significantly decreased in the AD brains.Conclusions: Although AD brains contain a net increase in DNA breaks, adaptive DNA breaks at nervous system genes are lost in AD brains. This could potentially reflect diminished TOP2B expression and contribute to impaired neuron function and cognition in AD patients.