TSC but not PTEN loss in starving cones of retinitis pigmentosa mice leads to an autophagy defect and mTORC1 dissociation from the lysosome.
TSC but not PTEN loss in starving cones of retinitis pigmentosa mice leads to an autophagy defect and mTORC1 dissociation from the lysosome.
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TSC，但在色素性视网膜炎小鼠的饥饿锥中的PTEN损失不会导致自噬缺陷和MTORC1与溶酶体的分离。
DOI：
10.1038/cddis.2016.182
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发表时间：
2016-06-30
影响因子：
9
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中科院分区：
文献类型：
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了解视网膜色素变性（RP）中继发性视锥细胞损失的机制对于制定延长这种神经退行性疾病视力的策略至关重要。我们以前表明，组成性激活哺乳动物靶雷帕霉素复合物1（mTORC 1），其负调节剂的结节性硬化症复合物蛋白1（Tsc1，也称为Hamartin）的损失，是足以促进强大的生存营养应激锥在两个小鼠模型的RP通过改善葡萄糖的摄取和利用。然而，虽然锥保护最初保持稳定的几个星期，最终锥损失恢复。在这里，我们表明，Tsc 1的RP小鼠的视锥细胞的损失导致自噬缺陷，导致泛素化聚集体的积累。我们证明，这种缺陷是不是由于自噬启动的抑制，但由于积累的自溶体，这表明在该过程的最后阶段的缺陷，造成氨基酸短缺的锥，从而阻碍长期锥生存。由于TSC缺失的细胞不能完全抑制mTORC1并在缺乏氨基酸的情况下适当地激活自噬，我们零星地施用mTORC1抑制剂雷帕霉素，这足以纠正视锥细胞中观察到的缺陷，进一步增强由Tsc 1缺失介导的视锥细胞存活的效率。一致地，通过磷酸酶和张力蛋白同源物（Pten）的丢失激活mTORC 1并不影响自噬和氨基酸代谢，导致对视锥细胞的更持续的长期保护。与Tsc1缺失相比，Pten缺失导致视锥细胞中mTORC1激活不太稳定，但仍能提供长期视锥细胞存活，因此使用mTORC1激活剂进行治疗干预或使用选定的mTORC1靶点进行基因治疗（改善葡萄糖代谢）是延缓RP患者视力丧失的潜在策略。
Understanding the mechanisms that contribute to secondary cone photoreceptor loss in retinitis pigmentosa (RP) is critical to devise strategies to prolong vision in this neurodegenerative disease. We previously showed that constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1), by loss of its negative regulator the tuberous sclerosis complex protein 1 (Tsc1; also known as Hamartin), was sufficient to promote robust survival of nutrient-stressed cones in two mouse models of RP by improving glucose uptake and utilization. However, while cone protection remained initially stable for several weeks, eventually cone loss resumed. Here we show that loss of Tsc1 in the cones of RP mice causes a defect in autophagy, leading to the accumulation of ubiquitinated aggregates. We demonstrate that this defect was not due to an inhibition of autophagy initiation, but due to an accumulation of autolysosomes, suggesting a defect in the end-stage of the process causing an amino-acid shortage in cones, thereby hampering long-term cone survival. Because cells with TSC loss fail to completely inhibit mTORC1 and properly activate autophagy in the absence of amino acids, we sporadically administered the mTORC1 inhibitor rapamycin, which was sufficient to correct the defects seen in cones, further enhancing the efficiency of cone survival mediated by Tsc1 loss. Concordantly, activation of mTORC1 by loss of the phosphatase and tensin homolog (Pten) did not affect autophagy and amino-acid metabolism, leading to a more sustained long-term protection of cones. As loss of Pten, which in cones results in less robust mTORC1 activation when compared with loss of Tsc1, still affords long-term cone survival, therapeutic interventions with mTORC1 activators or gene therapy with selected mTORC1 targets that improve glucose metabolism are potential strategies to delay vision loss in patients with RP.
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