Comitato Antonella, Di Salvo Maria Teresa, Turchiano Giandomenico, Montanari Monica, Sakami Sanae, Palczewski Krzysztof, Marigo Valeria
Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Hum Mol Genet. 2016 Jul 1;25(13):2801-2812. doi: 10.1093/hmg/ddw137. Epub 2016 May 5.
Mutations in rhodopsin (RHO) are a common cause of retinal dystrophy and can be transmitted by dominant or recessive inheritance. Clinical symptoms caused by dominant and recessive mutations in patients and animal models are very similar but the molecular mechanisms leading to retinal degeneration may differ. We characterized three murine models of retina degeneration caused by either Rho loss of function or expression of the P23H dominant mutation in Rho. Rho loss of function is characterized by activation of calpains and apoptosis-inducing factor (Aif) in dying photoreceptors. Retinas bearing the P23H dominant mutations activate both the calpain-Aif cell death pathway and ER-stress responses that together contribute to photoreceptor cell demise. In vivo treatment with the calpastatin peptide, a calpain inhibitor, was strongly neuroprotective in mice lacking Rho while photoreceptor survival in retinas expressing the P23H dominant mutation was more affected by treatment with salubrinal, an inhibitor of the ER-stress pathway. The further reduction of photoreceptor cell demise by co-treatment with calpastatin and salubrinal suggests co-activation of the calpain and ER-stress death pathways in mice bearing dominant mutations in the Rho gene.
视紫红质（RHO）突变是视网膜营养不良的常见病因，可通过显性或隐性遗传传递。患者及动物模型中由显性和隐性突变引起的临床症状非常相似，但导致视网膜变性的分子机制可能有所不同。我们对三种视网膜变性小鼠模型进行了特征描述，这些模型分别由Rho功能丧失或Rho中P23H显性突变的表达所致。Rho功能丧失的特征是在垂死的光感受器中钙蛋白酶和凋亡诱导因子（Aif）的激活。携带P23H显性突变的视网膜激活了钙蛋白酶-Aif细胞死亡途径和内质网应激反应，共同导致光感受器细胞死亡。用钙蛋白酶抑制肽（一种钙蛋白酶抑制剂）进行体内治疗，对缺乏Rho的小鼠具有很强的神经保护作用，而在用内质网应激途径抑制剂salubrinal治疗时，表达P23H显性突变的视网膜中的光感受器存活受到的影响更大。用钙蛋白酶抑制肽和salubrinal联合治疗进一步减少了光感受器细胞的死亡，这表明在Rho基因中携带显性突变的小鼠中，钙蛋白酶和内质网应激死亡途径共同激活。
