Fasullo Michael, Endres Lauren
Colleges of Nanoscale Sciences and Engineering, State University of New York Polytechnic University, Albany, NY 12203, USA.
Int J Mol Sci. 2015 Apr 27;16(5):9431-49. doi: 10.3390/ijms16059431.
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.
核苷酸平衡不仅在正在复制的细胞中至关重要，在静止细胞中同样如此。这在神经系统中尤为明显，神经系统对线粒体产生的三磷酸腺苷（ATP）有很高的需求。线粒体特别容易受到与氧化应激相关的DNA损伤，因为核苷酸失衡会由于低复制保真度而导致线粒体耗竭。由于遗传缺陷而未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。本综述比较了由特定核苷酸补救酶和DNA损伤暴露后激活核苷酸补救的信号激酶缺陷引起的遗传疾病。这些疾病包括莱施-奈恩综合征、线粒体耗竭综合征和共济失调毛细血管扩张症。虽然有治疗方法可缓解这些疾病的症状，但尚无治愈方法。本综述得出的结论包括鸟嘌呤核苷酸在预防神经退行性变中的关键作用、动物作为疾病模型的局限性以及在治疗方案中进一步了解核苷酸失衡的必要性。这些知识有望为未来遗传性疾病临床治疗的研究提供指导。
