Department of Cell Biology, Physiology, and Immunology, Institute of Neuroscience, Autonomous University of Barcelona, Bellaterra, Spain.
Biomedical Research Center Network on Neurodegenerative Diseases (CIBERNED), Bellaterra, Spain.
Neuro Oncol. 2021 Jan 30;23(1):88-99. doi: 10.1093/neuonc/noaa151.
Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development.
By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well-characterized neurophysiological mouse model of CIPN.
Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the upregulation of biological pathways related to DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-H2AX, and nuclear factor kappa B (Nfkb)-p65 proteins.
In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a nonfunctional senescence-like state.
顺铂诱导的周围神经病变（CIPN）是一种常见的严重剂量依赖性不良反应，可决定癌症治疗的剂量限制。CIPN 的严重程度与感觉神经元中检测到的铂量相关顺铂诱导的周围神经病变（CIPN）是一种常见的严重剂量依赖性不良反应，可决定癌症治疗的剂量限制。CIPN 的严重程度与感觉神经元中检测到的铂量相关顺铂诱导的周围神经病变（CIPN）是一种常见的严重剂量依赖性不良反应，可决定癌症治疗的剂量限制。CIPN 的严重程度与感觉神经元中检测到的铂量相关。然而，CIPN 的确切病理生理学机制尚不清楚，因此开发神经保护治疗的机会减少。本研究旨在确定 CIPN 发展中涉及的确切机制。
通过单细胞 RNA 测序（scRNAseq），我们研究了 CIPN 神经生理小鼠模型中感觉神经元的 DRG 转录组谱。
scRNAseq 数据的基因本体分析表明，顺铂处理诱导 DRG 神经元群体中与 DNA 损伤反应（DDR）相关的生物学途径上调。此外，DRG 神经元还上调了 Cdkn1a 基因，随后通过测量其蛋白产物 p21 得到证实。虽然在顺铂处理的小鼠 DRG 感觉神经元中未观察到细胞凋亡激活途径，但这些神经元确实表达了几种衰老特征，包括衰老相关的β-半乳糖苷酶、磷酸化 H2AX 和核因子 kappa B（Nfkb）-p65 蛋白。
在这项研究中，我们确定在顺铂诱导的 DNA 损伤后，p21 作为体内 DRG 感觉神经元中 DDR 的最相关下游因子出现，这些神经元以非功能样衰老状态存活。
