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- Title
Receptor Interacting Protein Kinase-Mediated Necrosis Contributes to Cone and Rod Photoreceptor Degeneration in the Retina Lacking Interphotoreceptor Retinoid-Binding Protein.
- Authors
Sato, Kota; Songhua Li; Gordon, William C.; He, Jibao; Liou, Gregory I.; Hill, James M.; Travis, Gabriel H.; Bazan, Nicolas G.; Jin, Minghao
- Abstract
Interphotoreceptor retinoid-binding protein (IRBP) secreted by photoreceptors plays a pivotal role in photoreceptor survival with an unknown mechanism. A mutation in the human IRBP has been linked to retinitis pigmentosa, a progressive retinal degenerative disease. Mice lacking IRBP display severe early and progressive photoreceptor degeneration. However, the signaling pathway(s) leading to photoreceptor death in IRBP-deficient mice remains poorly understood. Here, we show that amounts of tumor necrosis factor-α (TNF-α) in the interphotoreceptor matrix and retinas of Irbp-/-mice were increased more than 10-fold and fivefold, respectively, compared with those in wild-type mice. Moreover, TNF receptor 1, an important membrane death receptor that mediates both programmed apoptosis and necrosis, was also significantly increased in Irbp-/- retina, and was colocalized with peanut agglutinin to the Irbp-/- cone outer segments. Although these death signaling proteins were increased, the caspase-dependent and independent apoptotic pathways were mildly activated in the Irbp-/- retinas, suggesting that other cell death mechanism(s) also contributes to the extensive photoreceptor degeneration in Irbp-/- retina. We found that receptor interacting protein 1 and 3 (RIP1 and RIP3) kinases, the intracellular key mediators of TNF-induced cellular necrosis, were elevated at least threefold in the Irbp-/- retinas. Moreover, pharmacological inhibition of RIP1 kinase significantly prevented cone and rod photoreceptor degeneration in Irbp-/- mice. These results reveal that RIP kinase-mediated necrosis strongly contributes to cone and rod degeneration in Irbp-/- mice, implicating the TNF-RIP pathway as a potential therapeutic target to prevent or delay photoreceptor degeneration in patients with retinitis pigmentosa caused by IRBP mutation.
- Subjects
PROTEIN kinases; NECROSIS; RETINAL degeneration; INTERPHOTORECEPTOR retinoid-binding protein; PHOTORECEPTORS; DISEASE progression; LABORATORY mice
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 44, p17458
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1380-13.2013