Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis.
Increased carbonylation, protein aggregation and apoptosis in the spinal cord of mice with experimental autoimmune encephalomyelitis.
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DOI：
10.1042/an20120088
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发表时间：
2013
期刊：
影响因子：
4.7
通讯作者：
Bizzozero OA
中科院分区：
文献类型：
--
作者：
Dasgupta A;Zheng J;Perrone-Bizzozero NI;Bizzozero OA
我们实验室以前的工作涉及MS（多发性硬化症）及其动物模型EAE（实验性自身免疫性脑脊髓炎）的病理生理学中的蛋白质羰基化。随后的体外研究表明，由谷胱甘肽缺乏或蛋白酶体抑制引发的蛋白质羰基的积累导致蛋白质聚集和神经元细胞死亡。这些发现促使我们研究它们的关联是否也可以在体内建立。在本研究中，我们的特点是蛋白质羰基化，蛋白质聚集沿着C57 BL/6小鼠脊髓过程中的髓鞘-少突胶质细胞糖蛋白（MOG）35 - 55肽诱导的EAE。结果表明，蛋白质羰基在整个疾病过程中积累，尽管机制不同：急性EAE中氧化应激增加，慢性EAE中蛋白酶体活性降低。我们还显示了蛋白质羰基化（但不是氧化应激）和细胞凋亡之间的时间相关性。此外，凋亡细胞中的羰基水平显著高于活细胞。在EAE过程中，存在大量的近核和细胞质蛋白质聚集体，其中含有大多数氧化蛋白。LC3（微管相关蛋白轻链3）-II/LC3-I比率在急性和慢性EAE中均显著降低，表明自噬减少，并解释了为什么侵袭体在这种疾病中积累。总之，本研究的结果表明体内蛋白质氧化和神经元/神经胶质细胞死亡之间存在联系，并且还证明了在这种广泛使用的MS小鼠模型中蛋白质稳态受损。
Previous work from our laboratory implicated protein carbonylation in the pathophysiology of both MS (multiple sclerosis) and its animal model EAE (experimental autoimmune encephalomyelitis). Subsequent in vitro studies revealed that the accumulation of protein carbonyls, triggered by glutathione deficiency or proteasome inhibition, leads to protein aggregation and neuronal cell death. These findings prompted us to investigate whether their association can be also established in vivo. In the present study, we characterized protein carbonylation, protein aggregation and apoptosis along the spinal cord during the course of MOG (myelin-oligodendrocyte glycoprotein)35–55 peptide-induced EAE in C57BL/6 mice. The results show that protein carbonyls accumulate throughout the course of the disease, albeit by different mechanisms: increased oxidative stress in acute EAE and decreased proteasomal activity in chronic EAE. We also show a temporal correlation between protein carbonylation (but not oxidative stress) and apoptosis. Furthermore, carbonyl levels are significantly higher in apoptotic cells than in live cells. A high number of juxta-nuclear and cytoplasmic protein aggregates containing the majority of the oxidized proteins are present during the course of EAE. The LC3 (microtubule-associated protein light chain 3)-II/LC3-I ratio is significantly reduced in both acute and chronic EAE indicating reduced autophagy and explaining why aggresomes accumulate in this disorder. Taken together, the results of the present study suggest a link between protein oxidation and neuronal/glial cell death in vivo, and also demonstrate impaired proteostasis in this widely used murine model of MS.