本文节选自外刊《科学》系列（SCIENCE ADVANCES • 15 Apr 2022 • Vol 8, Issue 15）Tracing brain genotoxic stress in Parkinson’s disease with a novel single-cell genetic sensor——用新型单细胞遗传传感器追踪帕金森病患者的脑遗传毒性应激。
论文内容节选如下：
Tracing brain genotoxic stress in Parkinson’s disease with a novel single-cell genetic sensor
用新型单细胞遗传传感器追踪帕金森病患者的脑遗传毒性应激
To develop an in vivo tool to probe brain genotoxic stress, we designed a viral proxy as a single-cell genetic sensor termed PRISM that harnesses the instability of recombinant adeno-associated virus genome processing and a hypermutable repeat sequence–dependent reporter.
为了开发一种体内工具来探测大脑基因毒性应激，我们设计了一种病毒代理作为单细胞遗传传感器，称为PRISM，利用重组腺相关病毒基因组加工的不稳定性和一种高度可变的重复序列依赖性报告基因。
PRISM exploits the virus-host interaction to probe persistent neuronal DNA damage and overactive DNA damage response.
PRISM利用病毒-宿主相互作用来探测持续的神经元DNA损伤和过度活跃的DNA损伤反应。
A Parkinson’s disease (PD)–associated environmental toxicant, paraquat (PQ), inflicted neuronal genotoxic stress sensitively detected by PRISM.
一种帕金森氏病(PD)相关的环境毒物百草枯(PQ)引起神经元遗传毒性应激，PRISM敏感地检测到这种应激。
The most affected cell type in PD, dopaminergic (DA) neurons in substantia nigra, was distinguished by a high level of genotoxic stress following PQ exposure.
帕金森病中受影响最大的细胞类型，即黑质中的多巴胺能(DA)神经元，在PQ暴露后表现出高水平的遗传毒性应激。
Human alpha-synuclein proteotoxicity and propagation also triggered genotoxic stress in nigral DA neurons in a transgenic mouse model.
在转基因小鼠模型中，人类α-突触核蛋白的蛋白毒性和繁殖也在黑质多巴胺神经元中触发了基因毒性应激。
Genotoxic stress is a prominent feature in PD patient brains.
遗传毒性应激是帕金森病患者大脑的一个显著特征。
Our results reveal that PD-associated etiological factors precipitated brain genotoxic stress and detail a useful tool for probing the pathogenic significance in aging and neurodegenerative disorders.
我们的研究结果揭示了帕金森病相关的病因学因素促进了大脑的遗传毒性应激，并为探索衰老和神经退行性疾病的病因学意义提供了一个有用的工具。
重点词汇
genotoxic遗传毒性的
harnesses利用；控制；治理；披上甲胄；（harness的第三人称单数）；马具；挽具；安全带；甲胄；（harness的复数）
hypermutable超突变的
exploits功绩；勋绩；（exploit的复数）；剥削；开采；开拓；开发；（exploit的第三人称单数）
overactive过于活跃的
toxicant毒物；毒药
paraquat百草枯；对草快
sensitively敏感地；易感知地；慎重地；易受伤害地
dopaminergic多巴胺能的
substantia nigra黑质；黑质区
Most cases of neurodegenerative disorders (NDDs), such as Alzheimer’s (AD) and Parkinson’s diseases (PD), are idiopathic, with no identifiable inheritance, and occur in a sporadic form.
大多数神经退行性疾病(NDDs)，如阿尔茨海默病(AD)和帕金森病(PD)，都是特发性的，没有可识别的遗传，并以散发的形式发生。
Environmental risk factors have long been implicated in the etiology of sporadic NDDs.
长期以来，环境风险因素与散发性NDDs的病因学有关。
However, the causal evidence and mechanistic insights into the pathogenic role of environmental risk factors in NDDs are still mostly unknown.
然而，关于环境风险因素在NDDs中的致病作用的因果证据和机制见解仍然是未知的。
The recent discovery of nongermline inherited, somatic mutations in human brains provides further evidence associating environmental risk with the etiology of sporadic NDDs.
最近在人类大脑中发现的非基因遗传的体细胞突变提供了进一步的证据，将环境风险与散发性NDDs的病因学联系起来。
Age-dependent accumulation of somatic mutations has been associated with aging and neurodegenerative cases.
体细胞突变的年龄依赖性累积与衰老和神经退行性疾病有关。
Multiple studies have identified a low allele frequency of mutations of genes causing the familial form of NDDs in human brains.
多项研究已经确定了导致人类大脑中家族性NDDs的基因突变的低等位基因频率。
For example, mosaicism from the somatic mutation of presenilin-1 was identified in 14% of cortical cells in a patient with AD.
例如，在一名AD患者14%的皮质细胞中发现了来自早老素-1体细胞突变的镶嵌现象。
Somatic variants of β-amyloid precursor protein and somatic single-nucleotide variants (SNVs) affecting tau phosphorylation have also been reported.
还报道了β-淀粉样前体蛋白的体细胞变体和影响tau磷酸化的体细胞单核苷酸变体(SNVs)。
In addition, mosaic instability of the CAG repeat expansion in somatic tissues of Huntington’s disease (HD) mouse models and HD patient brains is associated with an earlier age of disease onset.
此外，亨廷顿氏病(HD)小鼠模型和HD患者脑的体组织中CAG重复扩增的镶嵌不稳定性与疾病发病年龄较早有关。
This has led to a hypothesis that somatic instability may contribute to disease progression.
这导致了一个假设，即躯体不稳定性可能有助于疾病的进展。
Somatic mosaicism of SNCA rearrangements and copy number variants (CNVs) were identified in patients with PD.
在帕金森病患者中发现了SNCA重排和拷贝数变异的体细胞镶嵌现象。
However, disease-relevant somatic coding variants have not been consistently detected in synucleinopathies.
然而，在共核蛋白病中并没有发现与疾病相关的体细胞编码变异。
重点词汇
neurodegenerative神经变性的
parkinson帕金森（姓氏）
idiopathic自发的；原发的；特发的；病因不明的
identifiable可辨认的；可识别的
sporadic散乱的；零星的
implicated牵涉；使卷入；影响；暗示；（implicate的过去式和过去分词）；有牵连的；涉案的；暗示的
mechanistic机械论的；机械性的
somatic躯体的；体腔的；与躯体有关的
associating联想；使联合；使发生联系；（associate的现在分词）；交往；结交
allele等位基因
Brain somatic mutations could arise in the developing embryo in the progenitor cells of neurons or glia through replication errors during S phase, which has been speculated to contribute to the origin of neurodevelopmental disorders.
大脑体细胞突变可通过S期复制错误在发育胚胎的神经元或神经胶质祖细胞中发生，这被推测为神经发育障碍的起源。
However, the age-dependent accumulation of unrepaired brain somatic mutations suggests that adult postmitotic neurons can acquire mutations as a result of persistent DNA damage (genotoxic stress).
然而，未修复的大脑体细胞突变的年龄依赖性积累表明，由于持续的DNA损伤(基因毒性应激)，成年有丝分裂后神经元可以获得突变。
Genotoxic stress could be elicited by endogenous factors, such as free radicals and peroxides generated during physiologic/pathologic processes, and environmental factors, e.g., exposure to toxic chemicals and physical agents in the environment.
遗传毒性应激可由内源性因素引发，如生理/病理过程中产生的自由基和过氧化物，以及环境因素，如暴露于环境中的有毒化学品和物理因子。
Known as a driver of cancer, low-dose environmental chemical exposure has been hypothesized to cause genomic instability, defined as higher-than-normal mutation rates, and precipitate somatic mosaicism in the adult brain.
作为癌症的驱动因素，低剂量环境化学暴露被假设为导致基因组不稳定，定义为高于正常的突变率，并促进成人大脑中的体细胞镶嵌。
For example, PD-related environmental toxicants, such as paraquat (PQ) and rotenone, have been linked to PD due to their ability to trigger redox cycling/oxidative stress that can cause damage to lipids, proteins, and DNA.
例如，与帕金森病相关的环境毒物，如百草枯(PQ)和鱼藤酮，已被认为与帕金森病有关，因为它们能够引发氧化还原循环/氧化应激，从而对脂质、蛋白质和DNA造成损害。
A recent study reported that humans with genetic variants of base excision repair (BER) genes are particularly vulnerable to PQ or rotenone exposure; BER variants synergize with PQ exposure to increase the risk of PD.
最近的一项研究报告说，具有碱基切除修复(BER)基因遗传变异的人特别容易受到PQ或鱼藤酮的影响；BER变异与PQ暴露协同增加帕金森病的风险。
Inefficient DNA repair is an age-related disease modifier.
低效的DNA修复是与年龄相关的疾病调节剂。
Together, these findings highlight genotoxic events driving somatic mutation and cellular response/dysfunction and their relevance to the pathogenesis of neurodegeneration.
总之，这些发现强调了驱动体细胞突变和细胞反应/功能障碍的基因毒性事件及其与神经变性发病机制的相关性。
重点词汇
progenitor祖先；创始人；先驱
speculated推测；（speculate的过去式）；投机；思索
postmitotic（细胞）有丝分裂期后的
genotoxic遗传毒性的
elicited引出；（elicit的过去式和过去分词）
free radicals自由基；游离基
peroxides过氧化物；（peroxide的复数）
physiologic生理的；生理学的
toxic chemicals有毒化学品；有毒化学物质；毒性化学品
hypothesized假设；假定；猜测；（hypothesize的过去式）
In response to DNA damage, eukaryotic cells have evolved a concerted signaling cascade, the DNA damage response (DDR), to recognize, signal, and repair DNA damage.
为了应对DNA损伤，真核细胞进化出了一种协同的信号级联反应，即DNA损伤反应(DDR)，以识别、信号传递和修复DNA损伤。
Persistent genotoxic stress triggers an overzealous DDR signaling cascade, dictating the fate of cells into apoptosis or senescence to prevent the replication of a damaged genome.
持续的基因毒性应激引发了过度活跃的DDR信号级联，决定了细胞凋亡或衰老的命运，以防止受损基因组的复制。
This serves as a safety mechanism to avoid cancer.
这是一种避免癌症的安全机制。
However, in postmitotic neurons, DDR-mediated cell cycle reentry and consequential apoptosis or cell senescence have been associated with aging and neurodegeneration.
然而，在有丝分裂后神经元中，DDR介导的细胞周期再进入和随之而来的凋亡或细胞衰老与衰老和神经变性有关。
New tools are needed to understand how brain genotoxic stress can elicit neurodegeneration.
我们需要新的工具来理解大脑基因毒性应激如何引发神经变性。
The current methods to study the impact of genotoxic stress focus on bulk or single-cell sequencing to seek disease mutations.
目前研究基因毒性应激影响的方法集中在整体或单细胞测序，以寻找疾病突变。
Such an approach has been, and will continue to be, critical and needs further improvement of detection sensitivity of very-low-frequency alleles and diverse types of mutations, including SNVs, CNVs, retrotransposon insertions, repeat expansions/contractions, aneuploidy, etc.
这种方法已经并将继续是至关重要的，需要进一步提高极低频等位基因和不同类型突变的检测灵敏度，包括SNVs、CNVs、逆转录转座子插入、重复扩增/收缩、非整倍体等。
Furthermore, heterogeneity of different cell types and brain regions may result in different vulnerabilities to the acquisition of mutations.
此外，不同细胞类型和大脑区域的异质性可能导致获得突变的不同脆弱性。
In addition, the small number of neurons with a deleterious somatic mutation(s) may have been long gone before the patient’s death.
此外，少数具有有害体细胞突变的神经元可能在患者死亡前早已消失。
Therefore, genetic tools enabling longitudinal tracking of the fate of cells with genotoxic stress (persistent DNA damage or increased DDR) may provide sufficient spatial and temporal resolution and sensitivity to track the neurons with environment-driven genotoxic stress and disentangle the cause-and-effect relation in NDDs.
因此，能够纵向追踪具有遗传毒性应激(持续DNA损伤或DDR增加)的细胞命运的遗传工具可以提供足够的空间和时间分辨率和灵敏度来追踪具有环境驱动的遗传毒性应激的神经元，并解开NDDs中的因果关系。
重点词汇
eukaryotic真核状态的
genotoxic遗传毒性的
triggers扳机；触发器；起动装置；能引起或促使一连串反应的事[物]；（trigger的复数）；引发；触发；扣…的扳机；（trigger的第三人称单数）
overzealous过分热心的
dictating使听写；命令；口述；（dictate的现在分词形式）；听写
senescence衰老；老化；细胞分裂和生长能力的丧失
postmitotic（细胞）有丝分裂期后的
reentry再进入；再入；再进；【法律】收回；【太空学】返回；再进张
consequential作为结果的；由…而起的；随之发生的；重要的；重大的；有重要意义的；间接发生的；间接引起的
elicit引出；引起；得出；使（潜在的东西）显现；诱出
To design a genetic sensor to probe neuronal cell DNA damage and its surveillance and repair machinery in response to global genotoxic stress, we exploited long-standing observations that genotoxic DNA damage can increase permissivity to AAV transduction due to the role of host cell DDR as an innate antiviral defense mechanism that is inhibitory to viral life cycles.
为了设计一种基因传感器来探测神经元细胞DNA损伤及其响应全球基因毒性应激的监视和修复机制，我们利用了长期以来的观察结果，即由于宿主细胞DDR作为抑制病毒生命周期的先天性抗病毒防御机制的作用，基因毒性DNA损伤可以增加AAV转导的许可性。
We, therefore, harnessed the single-strand recombinant adeno-associated virus (rAAV) genome processing mechanism and the instability of a hypermutable repeat sequence to detect brain genotoxic stress and visualize neurodegeneration in postmitotic differentiated neurons.
因此，我们利用单链重组腺相关病毒(rAAV)基因组加工机制和高变重复序列的不稳定性来检测脑基因毒性应激并观察有丝分裂后分化神经元的神经变性。
We demonstrated that our viral genetic probe is sensitive in detecting neurons with increased DDR mediated by the central orchestrator of DDR, ataxia-telangiectasia mutated (ATM).
我们证明了我们的病毒基因探针在检测由DDR的中枢指挥者，共济失调-毛细血管扩张突变(ATM)介导的DDR增加的神经元方面是敏感的。
Exposure to PQ, a PD-associated environmental toxicant, heightened neuronal genotoxic stress and elicited neuropathology revealed by single-cell analysis.
单细胞分析显示，暴露于PQ(一种PD相关的环境毒物)会增加神经元的遗传毒性应激并引发神经病理学。
The increased neuronal genotoxic stress was also probed in a humanized alpha-synuclein (aSyn) transgenic mouse model infused with aSyn preformed fibrils (PFFs).
还在注入了aSyn预制纤维(PFFs)的人源化α-突触核蛋白(aSyn)转基因小鼠模型中探测了增加的神经元遗传毒性应激。
Last, we confirmed that genotoxic stress is a prominent feature in human PD patient brains.
最后，我们证实了遗传毒性应激是人类帕金森病患者大脑的一个显著特征。
Our results revealed that environment toxicants and aSyn proteotoxicity could precipitate neuronal genotoxic stress and detailed a useful tool to study its pathogenic significance in PD.
我们的研究结果揭示了环境毒物和aSyn蛋白毒性可诱发神经元遗传毒性应激，并为研究其在帕金森病中的致病意义提供了有用的工具。
重点词汇
genotoxic遗传毒性的
antiviral抗病毒的；防病毒的；抗病毒药物
defense mechanism防御机制；防卫机制；防御机理
life cycles生命周期；生活周期
harnessed利用；控制；治理；披上甲胄；（harness的过去式和过去分词）
hypermutable超突变的
visualize想像；使可见；使显现
postmitotic（细胞）有丝分裂期后的
orchestrator管弦乐演奏家
ataxia共济失调
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