Nucleotide salvage deficiencies, DNA damage and neurodegeneration.
Nucleotide salvage deficiencies, DNA damage and neurodegeneration.
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DOI：
10.3390/ijms16059431
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发表时间：
2015-04-27
影响因子：
5.6
通讯作者：
Endres L
中科院分区：
文献类型：
--
作者：
Fasullo M;Endres L
核苷酸平衡不仅在复制细胞中而且在静止细胞中都是至关重要的。在神经系统中尤其如此，其中对线粒体产生的三磷酸腺苷（ATP）有很高的需求。线粒体特别容易发生氧化应激相关的DNA损伤，因为核苷酸不平衡可导致线粒体由于低复制保真度而耗竭。由于遗传缺陷而不能维持核苷酸平衡可导致婴儿死亡;然而，特定疾病的临床表现存在很大差异。这篇综述比较了遗传性疾病，导致特定的核苷酸补救酶和信号激酶，激活核苷酸补救DNA损伤暴露后的缺陷。这些疾病包括Lesch-Nyhan综合征、线粒体耗竭综合征和共济失调毛细血管扩张症。虽然有治疗方案可以减轻这些疾病的症状，但没有治愈的方法。本次综述得出的结论包括鸟嘌呤核苷酸在预防神经退行性变方面的关键作用、动物作为疾病模型的局限性以及进一步了解治疗方案中核苷酸失衡的必要性。这些知识将有望指导未来的遗传疾病临床治疗研究。
Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP) produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases.
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