Abstract：
Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5\',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.
摘要：
着色性干皮病（XP）是由DNA损伤的核苷酸切除修复缺陷引起的。这导致对紫外线过敏和增加皮肤癌风险，因为阳光诱导的光产品仍未修复。然而,许多XP患者也表现出早发性神经变性，导致过早死亡.神经变性的机制尚不清楚。这里,我们使用来自XP患者和健康亲属的多能干细胞研究XP神经变性，在神经元分化过程中对样品进行功能多组学。我们显示了5\'的大幅增加的水平，XP神经元DNA中的8-环嘌呤和8-氧代嘌呤继发于明显的氧化应激。此外，我们发现内质网应激反应上调，突变基因型的逆转与表型拯救有关。严重的,XP神经元表现出蛋白质清除泛素-蛋白酶体系统（UPS）的不适当下调。XP神经元模型中UPS活性的化学增强可改善表型，虽然不够。虽然需要更多的工作，这项研究提供了具有干预潜力的见解。
