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

Nature Neuroscience volume 12, pages 44–52 (2009)Cite this article

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.

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Figure 1: Rod death kinetics in the Rho−/− mouse.
Figure 2: Cone death kinetics.
Figure 3: Summary of rod and cone death kinetics.
Figure 4: Affymetrix microarray analysis.
Figure 5: P-mTOR in wild-type and degenerating retinae.
Figure 6: Upregulation of Hif-1α and GLUT1 in cones.
Figure 7: Increased levels of LAMP-2 at the lysosomal membrane.
Figure 8: Insulin levels affect cone survival.

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Acknowledgements

We thank J. Nathans for the cone-lacZ mouse line and the blue-cone opsin antibody. We are grateful to S. Tsang, M. Naash and J. Lem for the Pde6b−/−, P23H and Rho−/− mice, respectively. The LAMP-2 antibody, developed by B. Granger, was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the US National Institute of Child Health and Human Development and maintained by the University of Iowa. We thank J. Trimarchi, R. Kanadia, N. Perrimon, J. Zirin, M. Feany and C. Tabin for critical reading of the manuscript. This work was supported by the US National Institutes of Health (RO1 EY014466), Macular Vision Research Foundation, Foundation for Retinal Research, Howard Hughes Medical Institute, Merck and by an EMBO fellowship to C.P.

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Authors and Affiliations

  1. Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Claudio Punzo & Constance L Cepko

  2. The Research Institute at Nationwide Children's Hospital and the Ohio State University, 169 Westwood Road, Columbus, 43214, Ohio, USA

    Karl Kornacker

  3. Department of Ophthamology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Constance L Cepko

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  1. Claudio Punzo
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C.P. conducted the experiments and wrote the manuscript. K.K. performed computational microarray analysis. C.L.C. supervised the project and wrote the manuscript.

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Correspondence to Constance L Cepko.

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Punzo, C., Kornacker, K. & Cepko, C. Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nat Neurosci 12, 44–52 (2009). https://doi.org/10.1038/nn.2234

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