Coordination in the unfolded protein response during aging in outbred deer mice
Coordination in the unfolded protein response during aging in outbred deer mice
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DOI：
10.1016/j.exger.2020.111191
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发表时间：
2021-02-01
影响因子：
3.9
通讯作者：
Kiaris, H.
中科院分区：
文献类型：
--
作者：
Soltanmohammadi, E.;Farmaki, E.;Kiaris, H.
内质网（ER）应激与多种代谢病理、神经退行性变和衰老有关。虽然所产生的未折叠蛋白反应（UPR）的各种机制方面已经阐明，其在遗传多样性人群中的调控仍然难以捉摸。本研究比较了7月龄和2-3岁远交系马鹿和白鹿的肺、肝和脑中BiP/GRP 78、GRP 94和钙连接蛋白（CANX）的表达。伴侣蛋白的表达在物种、组织和年龄之间是高度可变的，这表明个体伴侣蛋白的表达水平在衰老过程中并不一致。尽管存在这种变化，但在伴侣蛋白表达之间保持了高度的协调，表明UPR的严格调节，这与其维持稳态的适应性活性一致。在检测到神经退行性变化的较老的Maniculatus的脑中，揭示了协调的丧失，特别是在BiP与GRP 94或钙连接蛋白之间，这表明去协调而不是异常表达与衰老中UPR的失调有关。这些发现强调了UPR参与衰老相关病理的发病，并表明除了表达水平外，协同激活可能对实现稳态具有重要意义。这些研究结果强调了遗传多样性模型的价值，并建议在探索与病理学的联系时，应考虑单个靶点表达水平之外的转录网络的协调。
Endoplasmic reticulum (ER) stress has been linked to various metabolic pathologies, neurodegeneration and aging. Although various mechanistic aspects of the resulting unfolded protein response (UPR) have been elucidated, its regulation in genetically diverse populations remains elusive. In the present study we evaluated the expression of chaperones BiP/GRP78, GRP94 and calnexin (CANX) in the lungs, liver and brain of 7 months old and 2-3 years old outbred deer mice P. maniculatus and P. leucopus. Chaperones' expression was highly variable between species, tissues and ages suggesting that levels of expression of individual chaperones do not change consistently during aging. Despite this variation, a high degree of coordination was maintained between chaperones' expression indicating the tight regulation of the UPR which is consistent with its adaptive activity to maintain homeostasis. In the brain though of older P. maniculatus, at which neurodegenerative changes were detected, loss of coordination was revealed, especially between BiP and either of GRP94 or calnexin which indicates that de-coordination rather than aberrant expression is linked to deregulation of the UPR in aging. These findings underscore the involvement of UPR in the onset of aging-related pathologies and suggest that beyond levels of expression, concerted activation may be of significance to attain homeostasis. These findings emphasize the value of genetically diverse models and suggest that beyond levels of expression of individual targets the coordination of transcriptional networks should be considered when links to pathology are explored.