Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa

Nat Neurosci. 2009 Jan;12(1):44-52. doi: 10.1038/nn.2234. Epub 2008 Dec 7.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animal Nutritional Physiological Phenomena
  • Animals
  • Autophagy
  • Carrier Proteins / metabolism*
  • Cell Death
  • Cell Survival / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 6 / deficiency
  • Insulin / deficiency
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microarray Analysis
  • Nutrition Disorders / physiopathology
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Retina / metabolism
  • Retinal Cone Photoreceptor Cells*
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinitis Pigmentosa / metabolism
  • Retinitis Pigmentosa / physiopathology*
  • Rhodopsin / deficiency
  • Rhodopsin / genetics
  • TOR Serine-Threonine Kinases
  • Time Factors
  • Transgenes

Substances

  • Carrier Proteins
  • Insulin
  • Rhodopsin
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Cyclic Nucleotide Phosphodiesterases, Type 6
  • Pde6b protein, mouse
  • Pde6g protein, mouse