Receptor interacting protein kinase mediates necrotic cone but not rod cell death in a mouse model of inherited degeneration.
Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.
Retina Service, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Yusuke
Y
Murakami
Hidetaka
H
Matsumoto
Miin
M
Roh
Jun
J
Suzuki
Toshio
T
Hisatomi
Yasuhiro
Y
Ikeda
Joan W
JW
Miller
Demetrios G
DG
Vavvas
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D009336:Necrosis; D060888:Real-Time Polymerase Chain Reaction; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000648:ultrastructure*; D017949:Retinal Cone Photoreceptor Cells / Q000201:enzymology* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
D017931:DNA Primers; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse