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。这会导致对紫外线过敏并增加皮肤癌的风险，因为阳光引起的光产品仍未得到修复。然而，许多 XP 患者还表现出早发性神经退行性变，这会导致过早死亡。神经退行性变的机制尚不清楚。在这里，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本进行功能性多组学研究。我们发现 XP 神经元 DNA 中 5',8-环嘌呤和 8-氧代嘌呤的水平显着增加，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相关。至关重要的是，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 活性的化学增强改善了表型，尽管还不够。尽管还需要做更多的工作，但这项研究提出了具有干预潜力的见解。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.