Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush.
Neuritin 1 promotes retinal ganglion cell survival and axonal regeneration following optic nerve crush.
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DOI：
10.1038/cddis.2015.22
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发表时间：
2015-02-26
影响因子：
9
通讯作者：
Clark AF
中科院分区：
文献类型：
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作者：
Sharma TP;Liu Y;Wordinger RJ;Pang IH;Clark AF
Neuritin 1（Nrn 1）是一种细胞外糖磷脂酰肌醇连接蛋白，其刺激中枢神经系统（CNS）中的轴突可塑性、树突分支和突触成熟。本研究的目的是评估Nrn 1对体外轴突切断的视网膜神经节细胞（RGC）和体内视神经挤压（ONC）小鼠模型的神经保护和轴突生长特性。与对照组相比，用重组hNRN 1处理的轴突切断的培养的RGC显著增加了RGC的存活21%（n=6-7，P<0.01），并且RGC中的神经突生长增加了141%（n=15，P<0.05）。与对照AAV 2-CAG-绿色荧光蛋白转导组相比，在ONC之前用AAV 2-CAG-hNRN 1转导RGC促进RGC存活（450%，n=3-7，P<0.05），并且显著地将RGC功能保留70%，直到挤压后28天（dpc）（n=6，P<0.05）。与对照组相比，治疗组28 dpc视网膜中RGC标记物、多剪接RNA结合蛋白（Rbpms; 73%，n=5-8，P<0.001）和生长锥标记物、生长相关蛋白43（Gap 43; 36%，n=3，P<0.01）的水平显著升高。与对照相比，在AAV 2-hNRN 1组的视神经内观察到Gap 43表达的显著增加（100%，n=5-6，P<0.05）。总之，Nrn 1在体外和体内轴突损伤后对轴突切断的RGC表现出神经保护、再生作用并保留了RGC功能。Nrn 1是CNS神经退行性疾病的潜在治疗靶点。
Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6–7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG–hNRN1 prior to ONC promoted RGC survival (450%, n=3–7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG–green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5–8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5–6, P<0.05) expression was observed within the optic nerves of the AAV2–hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.