title: Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa.
abstract: rhodopsin mutations result in autosomal dominant retinitis pigmentosa (ADRP), the most frequent being Proline-23 substitution by histidine (RhoP23H). Although cellular and rodent animal models have been developed, the pathogenic mechanisms leading to RhoP23H-induced cell death are still poorly understood. For this, we have used a Drosophila model by introducing a mutation in the fly rhodopsin-1 gene (Rh1P37H) that corresponds to human RhoP23H. Rh1P37H transgenic flies show dominant photoreceptor degeneration that mimics age-, light-dependent and progressive ADRP. Moreover, we clarify the pathogenic mechanism of Rh1P37H mutation that acts as an antimorph. First, we show the dual-localization of mutant Rhodopsin since most of Rh1P37H accumulates in endoplasmic reticulum. Second, expression of mutant, mislocalized, Rhodopsin leads to cytotoxicity, via the activation of two stress-specific mitogen-activated protein kinases (MAPKs), p38 and JNK, which are known to control stress-induced apoptosis. In Rh1P37H flies, visual loss and degeneration are indeed accompanied by apoptotic features and prevented by expression of p35 apoptosis inhibitor. Finally, we show for the first time that properly localized, mutant, Rhodopsin is active. Thus, the development of a fly model that faithfully reproduces the human disease sheds light onto the molecular defects causing ADRP thereby making it possible to devise potential therapeutic approaches.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Michel Joseph
authors.initials: MJ
authors.lastname: Roux
authors.forename: José Alain
authors.initials: JA
authors.lastname: Sahel
authors.forename: Thierry
authors.initials: T
authors.lastname: Léveillard
authors.forename: Angela
authors.initials: A
authors.lastname: Giangrande
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D016923:Cell Death; D004175:Diptera / Q000235:genetics*; D004195:Disease Models, Animal; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010786:Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics*
chemical_list: D012243:Rhodopsin