Abstract
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.
Highlights
The disintegration of neuronal networks owing to the nonautonomous death of neurons without primary damage is a hallmark manifestation of many neurodegenerative diseases and contributes determinately to their onset or progression [1,2,3]
We employed the multifunctional protein, Ran-binding protein-2 (Ranbp2), which is implicated in cell-type and stressdependent clinical manifestations, to examine its role(s) in primary and secondary photoreceptor death mechanisms upon its specific loss in cones
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
Summary
The disintegration of neuronal networks owing to the nonautonomous death of neurons without primary damage is a hallmark manifestation of many neurodegenerative diseases and contributes determinately to their onset or progression [1,2,3]. Cone or rod photoreceptor neurons employ cell type-specific spectrally tuned and highly homologous phototransduction cascades. Neurodegenerative disorders affecting these neurons serve as excellent models to understand autonomous and nonautonomous cell death processes. Rod photoreceptor-specific mutations causing the death of rod photoreceptors promote the non-autonomous death of cone photoreceptors [3,9,10,11,12]. This secondary loss of cone photoreceptors has the greatest impact on human vision, because cone photoreceptors mediate daylight and high acuity vision as well as color perception. Rod photoreceptor-specific mutations affecting phototransduction components of rod photo-
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