Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Neurobiol Dis. 2023 Nov;188:106331. doi: 10.1016/j.nbd.2023.106331. Epub 2023 Oct 18.
Under normal conditions, heat shock proteins work in unison through dynamic protein interactions collectively referred to as the "chaperome." Recent work revealed that during cellular stress, the functional interactions of the chaperome are modified to form the "epichaperome," which results in improper protein folding, degradation, aggregation, and transport. This study is the first to investigate this novel mechanism of protein dishomeostasis in traumatic brain injury (TBI). Male and female adult, Sprague-Dawley rats received a lateral controlled cortical impact (CCI) and the ipsilateral hippocampus was collected 24 h 1, 2, and 4 weeks after injury. The epichaperome complex was visualized by measuring HSP90, HSC70 and HOP expression in native-PAGE and normalized to monomeric protein expression. A two-way ANOVA examined the effect of injury and sex at each time-point. Native HSP90, HSC70 and HOP protein expression showed a significant effect of injury effect across all time-points. Additionally, HSC70 and HOP showed significant sex effects at 24 h and 4 weeks. Altogether, controlled cortical impact significantly increased formation of the epichaperome across all proteins measured. Further investigation of this pathological mechanism can lead to a greater understanding of the link between TBI and increased risk of neurodegenerative disease and targeting the epichaperome for therapeutics.
在正常情况下，热休克蛋白通过被称为“伴侣组”的动态蛋白质相互作用协同工作。最近的研究表明，在细胞应激期间，伴侣组的功能相互作用会被修改，形成“表观伴侣组”，导致蛋白质错误折叠、降解、聚集和运输。本研究首次研究了创伤性脑损伤（TBI）中这种新的蛋白质失衡机制。雄性和雌性成年 Sprague-Dawley 大鼠接受了横向控制皮质撞击（CCI），并在损伤后 24 小时 1、2 和 4 周收集同侧海马体。通过测量天然 PAGE 中的 HSP90、HSC70 和 HOP 表达，并与单体蛋白表达归一化，来可视化表观伴侣组复合物。双向方差分析检查了每个时间点损伤和性别的影响。天然 HSP90、HSC70 和 HOP 蛋白表达在所有时间点均显示出损伤效应的显著影响。此外，HSC70 和 HOP 在 24 小时和 4 周时表现出显著的性别效应。总之，皮质控制撞击显著增加了所有测量蛋白的表观伴侣组的形成。对这种病理机制的进一步研究可以更好地理解 TBI 与神经退行性疾病风险增加之间的联系，并针对表观伴侣组进行治疗。
