Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa.
Retinitis pigmentosa is an incurable retinal disease that leads to blindness. One puzzling aspect concerns the progression of the disease. Although most mutations that cause retinitis pigmentosa are in rod photoreceptor-specific genes, cone photoreceptors also die as a result of such mutations. To understand the mechanism of non-autonomous cone death, we analyzed four mouse models harboring mutations in rod-specific genes. We found changes in the insulin/mammalian target of rapamycin pathway that coincided with the activation of autophagy during the period of cone death. We increased or decreased the insulin level and measured the survival of cones in one of the models. Mice that were treated systemically with insulin had prolonged cone survival, whereas depletion of endogenous insulin had the opposite effect. These data suggest that the non-autonomous cone death in retinitis pigmentosa could, at least in part, be a result of the starvation of cones.
Punzo
Claudio
C
Harvard Medical School, Department of Genetics and Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Kornacker
Karl
K
Cepko
Constance L
CL
D019943:Amino Acid Substitution; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000172:deficiency; D007328:Insulin / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009748:Nutrition Disorders / Q000503:physiopathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D012160:Retina / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000378:metabolism / Q000503:physiopathology*; D012243:Rhodopsin / Q000172:deficiency / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D019076:Transgenes
D002352:Carrier Proteins; D007328:Insulin; D012243:Rhodopsin; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse; C517444:Pde6g protein, mouse