Distinct and atypical intrinsic and extrinsic cell death pathways between photoreceptor cell types upon specific ablation of Ranbp2 in cone photoreceptors

• Published in: PLoS genetics Vol. 9; no. 6; p. e1003555
• Main Authors: Cho, Kyoung-In, Haque, Mdemdadul, Wang, Jessica, Yu, Minzhong, Hao, Ying, Qiu, Sunny, Pillai, Indulekha C L, Peachey, Neal S, Ferreira, Paulo A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2013; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Biology; Cell death; Cell Death - genetics; Cell Lineage; Colleges & universities; Degeneration; Gene expression; Genetic aspects; Health aspects; Health sciences; Humans; Light; Mice; Mice, Transgenic; Microscopy; Molecular Chaperones - genetics; Nerve Net - metabolism; Nervous system; Neural networks; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - pathology; Nuclear Pore Complex Proteins - genetics; Photoreceptors; Physiological aspects; Proteins; Retina - metabolism; Retina - pathology; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal Degeneration - genetics; Retinal Degeneration - pathology; Retinal Rod Photoreceptor Cells - cytology; Retinal Rod Photoreceptor Cells - metabolism; Up-Regulation; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003555

Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2), a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+ -apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct retinal spatial signatures as well as with other etiologically distinct neurodegenerative disorders.