Venkatesh Aditya, Ma Shan, Le Yun Z, Hall Michael N, Rüegg Markus A, Punzo Claudio
J Clin Invest. 2015 Apr;125(4):1446-58. doi: 10.1172/JCI79766. Epub 2015 Mar 23.
Retinitis pigmentosa (RP) is an inherited photoreceptor degenerative disorder that results in blindness. The disease is often caused by mutations in genes that are specific to rod photoreceptors; however, blindness results from the secondary loss of cones by a still unknown mechanism. Here, we demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) is required to slow the progression of cone death during disease and that constitutive activation of mTORC1 in cones is sufficient to maintain cone function and promote long-term cone survival. Activation of mTORC1 in cones enhanced glucose uptake, retention, and utilization, leading to increased levels of the key metabolite NADPH. Moreover, cone death was delayed in the absence of the NADPH-sensitive cell death protease caspase 2, supporting the contribution of reduced NADPH in promoting cone death. Constitutive activation of mTORC1 preserved cones in 2 mouse models of RP, suggesting that the secondary loss of cones is caused mainly by metabolic deficits and is independent of a specific rod-associated mutation. Together, the results of this study address a longstanding question in the field and suggest that activating mTORC1 in cones has therapeutic potential to prolong vision in RP.
视网膜色素变性（RP）是一种遗传性光感受器退行性疾病，可导致失明。该疾病通常由视杆光感受器特有的基因突变引起；然而，失明是由视锥细胞通过一种仍不清楚的机制继发性丧失所致。在此，我们证明哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）是减缓疾病过程中视锥细胞死亡进展所必需的，并且视锥细胞中mTORC1的组成性激活足以维持视锥细胞功能并促进视锥细胞长期存活。视锥细胞中mTORC1的激活增强了葡萄糖摄取、保留和利用，导致关键代谢物NADPH水平升高。此外，在缺乏对NADPH敏感的细胞死亡蛋白酶caspase 2的情况下，视锥细胞死亡延迟，这支持了NADPH减少在促进视锥细胞死亡中的作用。mTORC1的组成性激活在2种RP小鼠模型中保留了视锥细胞，表明视锥细胞的继发性丧失主要是由代谢缺陷引起的，并且独立于特定的视杆相关突变。总之，本研究结果解决了该领域一个长期存在的问题，并表明在视锥细胞中激活mTORC1具有延长RP患者视力的治疗潜力。
