Department of Neurology, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany
Neurobiol Dis. 2012 May;46(2):314-24. doi: 10.1016/j.nbd.2012.01.004. Epub 2012 Jan 20.
Mature retinal ganglion cells (RGCs) do not normally regenerate injured axons, but degenerate after axotomy. However, inflammatory stimulation (IS) enables RGCs to survive axotomy and regenerate axons in the injured optic nerve. Similar effects are achieved by the genetic deletion of phosphatase and tensin homolog (PTEN) and subsequent mammalian target of rapamycin (mTOR) activation. Here, we report that IS prevents the axotomy-induced decrease of mTOR activity in RGCs in a CNTF/LIF-dependent manner. Inactivation of mTOR significantly reduced the number of long axons regenerating in the optic nerve, but surprisingly, did not affect the initial switch of RGCs into the regenerative state, or the neuroprotective effects associated with IS. In vitro, inhibition of mTOR activity reduced regeneration on myelin or chondroitin sulfate proteoglycans (CSPGs), but not on a growth-permissive substrate. Thus, mTOR activity is not generally required for neuroprotection or switching mature neurons into an active regenerative state, but it is important for the maintenance of the axonal growth state and overcoming of inhibitory effects caused by myelin and CSPGs.
成熟的视网膜神经节细胞（RGCs）通常不会再生受损的轴突，但在轴突切断后会退化。然而，炎症刺激（IS）使 RGCs 能够在受损的视神经中存活并再生轴突。通过删除磷酸酶和张力蛋白同源物（PTEN）并随后激活哺乳动物雷帕霉素靶蛋白（mTOR），可以达到类似的效果。在这里，我们报告说，IS 以 CNTF/LIF 依赖性的方式防止了轴突切断诱导的 RGCs 中 mTOR 活性的降低。mTOR 的失活显著减少了视神经中再生的长轴突的数量，但令人惊讶的是，它并不影响 RGCs 最初进入再生状态的转换，或与 IS 相关的神经保护作用。在体外，抑制 mTOR 活性会减少在髓鞘或软骨素硫酸盐蛋白聚糖（CSPGs）上的再生，但不会减少在生长允许的基质上的再生。因此，mTOR 活性通常不需要用于神经保护或将成熟神经元转换为活跃的再生状态，但它对于维持轴突生长状态和克服髓鞘和 CSPGs 引起的抑制作用很重要。
