Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response
Calls, Aina (Universitat Autònoma de Barcelona. Institut de Neurociències)
Torres Espín, Abel (University of California)
Navarro, X. (Xavier) (Universitat Autònoma de Barcelona. Institut de Neurociències)
Yuste, Victor J.. (Universitat Autònoma de Barcelona. Institut de Neurociències)
Udina i Bonet, Esther (Universitat Autònoma de Barcelona. Institut de Neurociències)
Bruna, Jordi (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data:	2020
Resum:	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. Methods: 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. Results :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. Conclusions: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.
Ajuts:	Instituto de Salud Carlos III PI1501303
Nota:	Altres ajuts: Departament de Salut, programa CERCA SLT008/18/00028
Drets:	Tots els drets reservats.
Llengua:	Anglès
Document:	Article ; recerca ; Versió sotmesa a revisió
Publicat a:	Neuro-Oncology, Vol. 23, Num. 1 (jan. 2021) , p. 88-99, ISSN 1523-5866

Adreça alternativa: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850121/
DOI: 10.1093/neuonc/noaa151
PMID: 32597980

43 p, 3.5 MB

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