Leung Emily, Taskina Daria, Schwab Nicole, Hazrati Lili-Naz
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
Front Neurosci. 2023 Aug 10;17:1225226. doi: 10.3389/fnins.2023.1225226. eCollection 2023.
Emerging evidence suggests cellular senescence, as a consequence of excess DNA damage and deficient repair, to be a driver of brain dysfunction following repeated mild traumatic brain injury (rmTBI). This study aimed to further investigate the role of deficient DNA repair, specifically BRCA1-related repair, on DNA damage-induced senescence. BRCA1, a repair protein involved in maintaining genomic integrity with multiple roles in the central nervous system, was previously reported to be significantly downregulated in post-mortem brains with a history of rmTBI. Here we examined the effects of impaired BRCA1-related repair on DNA damage-induced senescence and outcomes 1-week post-rmTBI using mice with a heterozygous knockout for BRCA1 in a sex-segregated manner. Altered BRCA1 repair with rmTBI resulted in altered anxiety-related behaviours in males and females using elevated zero maze and contextual fear conditioning. Evaluating molecular markers associated with DNA damage signalling and senescence-related pathways revealed sex-specific differences attributed to BRCA1, where females exhibited elevated DNA damage, impaired DNA damage signalling, and dampened senescence onset compared to males. Overall, the results from this study highlight sex-specific consequences of aberrant DNA repair on outcomes post-injury, and further support a need to develop sex-specific treatments following rmTBI.
新出现的证据表明，细胞衰老作为DNA损伤过多和修复不足的结果，是反复轻度创伤性脑损伤（rmTBI）后脑功能障碍的一个驱动因素。本研究旨在进一步探讨DNA修复缺陷，特别是与BRCA1相关的修复，在DNA损伤诱导的衰老中的作用。BRCA1是一种参与维持基因组完整性的修复蛋白，在中枢神经系统中具有多种作用，先前有报道称，在有rmTBI病史的尸检大脑中，BRCA1显著下调。在这里，我们以性别隔离的方式，使用BRCA1杂合敲除小鼠，研究了BRCA1相关修复受损对DNA损伤诱导的衰老和rmTBI后1周结果的影响。rmTBI导致的BRCA1修复改变，在使用高架零迷宫和情境恐惧条件反射时，导致雄性和雌性的焦虑相关行为发生改变。评估与DNA损伤信号传导和衰老相关途径相关的分子标记物，发现了归因于BRCA1的性别特异性差异，与雄性相比，雌性表现出更高的DNA损伤、受损的DNA损伤信号传导和延迟的衰老起始。总体而言，本研究结果突出了异常DNA修复对损伤后结果的性别特异性影响，并进一步支持了在rmTBI后开发性别特异性治疗方法的必要性。
