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. Author Summary The secondary demise of healthy neurons upon the degeneration of neurons harboring primary genetic defect(s) is hallmark to neurodegenerative diseases. However, the factors and mechanisms driving these cell-death processes are not understood, a severe limitation which has hampered the therapeutic development of neuroprotective approaches. The neuroretina is comprised of two main types of photoreceptor neurons, rods and cones. These undergo degeneration upon heterogeneous mutations or environmental stressors and the underlying diseases present conspicuous spatiotemporal pathological signatures whose molecular bases are not understood. We employed the multifunctional protein, Ran-binding protein-2 (Ranbp2), which is implicated in cell-type and stress-dependent clinical manifestations, to examine its role(s) in primary and secondary photoreceptor death mechanisms upon its specific loss in cones. Contrary to prior findings, we found that dying cones can trigger the loss of healthy rods. This process arises by the immediate activation of novel Ranbp2-responsive factors and downstream cascade events in cones that promote extrinsically the demise of rods. The mechanisms of rod and cone demise are molecularly distinct. Collectively, the data uncover distinct Ranbp2 roles in intrinsic and extrinsic cell-death and will likely contribute to our understanding of the spatiotemporal onset and progression of diseases affecting photoreceptor mosaics and other neural networks.
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