Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration
Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration
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DOI：
10.1073/pnas.1616811114
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发表时间：
2017-01-10
影响因子：
11.1
通讯作者：
Benowitz, Larry
中科院分区：
文献类型：
--
作者：
Li, Yiqing;Andereggen, Lukas;Benowitz, Larry
一旦视神经受损，视网膜神经节细胞（RGC）即眼睛的投射神经元就无法再生轴突，并很快开始死亡。尽管 RGC 死亡和再生失败被广泛认为是细胞自主的或受各种类型神经胶质细胞的影响，但我们在此报告，视网膜中间神经元中移动锌 (Zn2+) 的失调是一个主要因素。视神经损伤后一小时内，视网膜无长突细胞突中的 Zn2+ 增加数倍，并在第一天继续增加，然后通过囊泡释放缓慢转移至 RGC。无长突细胞过程中 Zn2+ 的积累涉及 Zn2+ 转运蛋白 ZnT-3，编码 ZnT-3 的基因 slc30a3 的缺失可促进 RGC 存活和轴突再生。玻璃体内注射 Zn2+ 螯合剂可使许多 RGC 在神经损伤后存活数月并再生轴突，并增强删除磷酸酶和张力蛋白同源物 (pten) 基因的促生存和再生作用。重要的是，Zn2+螯合的治疗窗口在神经损伤后可延长几天。这些结果表明，视网膜 Zn2+ 失调是限制受损 RGC 存活和再生能力的主要因素，并指出 Zn2+ 螯合是促进长期 RGC 保护和增强轴突再生的策略。
Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die. Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+ accumulation in amacrine cell processes involves the Zn2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+ chelation extends for several days after nerve injury. These results show that retinal Zn2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.