Department of Biochemistry and Biomedical Sciences, McMaster University, HSC 4N54, 1200 Main Street West, Hamilton, Ontario, L8N3Z5, Canada.
Neurotherapeutics. 2019 Oct;16(4):948-956. doi: 10.1007/s13311-019-00768-7.
Recent genome-wide association studies of Huntington's disease (HD) primarily highlighted genes involved in DNA damage repair mechanisms as modifiers of age at onset and disease severity, consistent with evidence that more DNA repair genes are being implicated in late age-onset neurodegenerative diseases. This provides an exciting opportunity to advance therapeutic development in HD, as these pathways have already been under intense investigation in cancer research. Also emerging are the roles of other polyglutamine disease proteins in DNA damage repair mechanisms. A potential universal trigger of oxidative DNA damage shared in these late age-onset diseases is the increase of reactive oxygen species (ROS) in human aging, defining an age-related mechanism that has defied other hypotheses of neurodegeneration. We discuss the potential commonality of DNA damage repair pathways in HD and other neurodegenerative diseases. Potential targets for therapy that may prove beneficial across many of these diseases are also identified, defining nodes in the ataxia telangiectasia-mutated (ATM) complex, mismatch repair, and poly ADP-ribose polymerases (PARPs).
最近对亨廷顿病 (HD) 的全基因组关联研究主要强调了参与 DNA 损伤修复机制的基因是发病年龄和疾病严重程度的调节剂，这与越来越多的 DNA 修复基因参与晚发性神经退行性疾病的证据一致。这为 HD 的治疗开发提供了一个令人兴奋的机会，因为这些途径在癌症研究中已经受到了强烈的关注。其他多聚谷氨酰胺疾病蛋白在 DNA 损伤修复机制中的作用也在不断涌现。这些晚发性疾病中共同存在的氧化 DNA 损伤的潜在普遍触发因素是人类衰老中活性氧 (ROS) 的增加，这定义了一种与神经退行性变的其他假说相悖的与年龄相关的机制。我们讨论了 HD 和其他神经退行性疾病中 DNA 损伤修复途径的潜在共性。还确定了可能对这些疾病中的许多疾病都有益的潜在治疗靶点，这些靶点定义了共济失调毛细血管扩张突变 (ATM) 复合物、错配修复和聚 ADP-核糖聚合酶 (PARPs) 中的节点。
