Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration.
Axonal protection by Nmnat3 overexpression with involvement of autophagy in optic nerve degeneration.
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DOI：
10.1038/cddis.2013.391
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发表时间：
2013-10-17
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
轴突变性通常导致神经元细胞体的死亡。以前的研究表明，至关重要的作用，烟酰胺单核苷酸腺苷酸转移酶（Nmnat）1，2和3轴突保护。在这项研究中，Nmnat 3免疫反应性内的视神经轴突观察。Nmnat 3过表达对肿瘤坏死因子诱导的视神经变性和眼内压升高诱导的视神经变性具有轴突保护作用。免疫印迹分析表明，p62和微管相关蛋白轻链3（LC 3）-II上调后，眼压升高的视神经。nmnat 3转染减少p62和增加LC 3-II在视神经与实验性青光眼。电子显微镜显示青光眼、青光眼+Nmnat 3转染和青光眼+雷帕霉素组中视神经轴突中存在自噬空泡，尽管在青光眼+Nmnat 3转染和青光眼+雷帕霉素组中注意到保留的髓鞘和微管结构。Nmnat 3的轴突保护作用被3-甲基腺嘌呤抑制，而雷帕霉素在眼压升高后发挥轴突保护作用。我们发现p62存在于线粒体中，并证实了在饥饿的视网膜神经节细胞（RGC）-5细胞中线粒体Nmnat 3和p62的实质性共定位。Nmnat 3转染降低了RGC-5细胞中的p62，增加了自噬通量。这些结果表明，Nmnat 3的轴突保护作用可能涉及自噬机制，并且Nmnat 3和自噬的调节可能导致针对退行性视神经疾病的潜在策略。
Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.
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影响因子：
9
作者：
通讯作者：
--
影响因子：
4.5
作者：
Libby RT;Li Y;Savinova OV;Barter J;Smith RS;Nickells RW;John SW
通讯作者：
John SW
影响因子：
5.3
作者：
Press, Craig;Milbrandt, Jeffrey
通讯作者：
Milbrandt, Jeffrey
影响因子：
4.8
作者：
Kitaoka, Yasushi;Munemasa, Yasunari;Ueno, Satoki
通讯作者：
Ueno, Satoki
影响因子：
4.4
作者：
Kitaoka, Y;Kitaoka, Y;Lam, TT
通讯作者：
Lam, TT