Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.

缺乏核苷酸切除修复 (NER) 的人类遗传综合征，如色素性干皮病和 Cockayne 综合征，可能会出现神经异常和过早衰老症状。阻碍转录的未修复的内源性 DNA 损伤是一个强有力的候选者，有助于在神经元组织中产生这些严重影响。内源性损伤包括由于细胞代谢的副产物产生的损伤，例如活性氧。这篇综述提供了许多关于与 DNA 损伤反应相关的神经退行性过程相关机制的证据。主要关注转录机制的影响，包括 DNA•RN​​A 杂合体（R-loops）的积累，进而影响 DNA 损伤和修复代谢。而且，一些神经元组织呈现出更高的长基因表达，这是一个受 DNA 损伤影响更大的基因组亚群，这可能解释了这些患者的部分神经系统异常。此外，神经元组织具有不同的 DNA 修复能力，可能导致不同的神经系统后果，如在患者和 NER 缺陷动物模型中观察到的那样。更好地了解转录阻断病变的积累如何导致神经系统异常和过早衰老样表型可能有助于我们找到可能改善这些患者以及一般其他神经系统疾病生活的潜在生物标志物和治疗靶点人口。正如在患者和 NER 缺陷动物模型中所观察到的，神经元组织具有不同的 DNA 修复能力，可能导致不同的神经学后果。更好地了解转录阻断病变的积累如何导致神经系统异常和过早衰老样表型可能有助于我们找到可能改善这些患者以及一般其他神经系统疾病生活的潜在生物标志物和治疗靶点人口。正如在患者和 NER 缺陷动物模型中所观察到的，神经元组织具有不同的 DNA 修复能力，可能导致不同的神经学后果。更好地了解转录阻断病变的积累如何导致神经系统异常和过早衰老样表型可能有助于我们找到可能改善这些患者以及一般其他神经系统疾病生活的潜在生物标志物和治疗靶点人口。