title: Dominant and recessive mutations in rhodopsin activate different cell death pathways.
abstract: 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.
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Comitato
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Di Salvo
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Turchiano
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Montanari
authors.affiliation: Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Sanae
authors.initials: S
authors.lastname: Sakami
authors.affiliation: Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy valeria.marigo@unimore.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Marigo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D051379:Mice; D009154:Mutation; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D002135:Calcium-Binding Proteins; C033668:calpastatin; D012243:Rhodopsin; D002154:Calpain