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Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

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Related in: MedlinePlus

Temporal profile of remodeling in light induced retinal damage. A schematic of the fraction of retinas displaying remodeling attributes (see Table 3) displayed on an exponential time scale. Immediately after light exposure, all retinas show massive stress signals, but by pLX 120 these are no longer evident. Müller cell seals form rapidly after light exposure and persist. Breakdown of the seal can be detected by pLX 14 and increases with time. Classic remodeling phenomena such as migration and microneuromas are evident by pLX60 but decline after emigration and retinal decimation become dominant.
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f19: Temporal profile of remodeling in light induced retinal damage. A schematic of the fraction of retinas displaying remodeling attributes (see Table 3) displayed on an exponential time scale. Immediately after light exposure, all retinas show massive stress signals, but by pLX 120 these are no longer evident. Müller cell seals form rapidly after light exposure and persist. Breakdown of the seal can be detected by pLX 14 and increases with time. Classic remodeling phenomena such as migration and microneuromas are evident by pLX60 but decline after emigration and retinal decimation become dominant.

Mentions: Environmental or inherited insults that kill photoreceptors are sensory deafferentations with the potential to trigger neural remodeling including neuronal loss, growth of new neurites, formation of new synapses, and even somatic migration. LIRD is a fast, effective trigger of large-scale remodeling (perhaps due to the high temporal coherence of the insult) that replicates and then progresses past phase III remodeling to ultimately decimate the neural retina (Figure 19). LIRD will enable detailed study of circuitry defects emergent from remodeling [5,6]. Moreover, the LIRD model presents derangements of cellular functions ranging from energetics (aspartate stress), osmoregulation (taurine dysregulation), retinoid processing (CRALBP expression fluctuations), global protein translation modulation (arginine upregulation), to glioma-like changes in glutamine metabolism. Collectively, these data demonstrate that LIRD models exhibit pathological processes observed in other retinal degenerative diseases and a variety of general neurodegenerations and neoplastic transformations. The LIRD model is a highly practical model for mimicking degenerative retinal disease without complicating developmental side-effects. Finally, the LIRD model is the only available model exhibiting all of the hallmarks of AMD including choroidal ablation, RPE ablation, photoreceptor cell death and retinal decimation.


Extreme retinal remodeling triggered by light damage: implications for age related macular degeneration.

Marc RE, Jones BW, Watt CB, Vazquez-Chona F, Vaughan DK, Organisciak DT - Mol. Vis. (2008)

Temporal profile of remodeling in light induced retinal damage. A schematic of the fraction of retinas displaying remodeling attributes (see Table 3) displayed on an exponential time scale. Immediately after light exposure, all retinas show massive stress signals, but by pLX 120 these are no longer evident. Müller cell seals form rapidly after light exposure and persist. Breakdown of the seal can be detected by pLX 14 and increases with time. Classic remodeling phenomena such as migration and microneuromas are evident by pLX60 but decline after emigration and retinal decimation become dominant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2375357&req=5

f19: Temporal profile of remodeling in light induced retinal damage. A schematic of the fraction of retinas displaying remodeling attributes (see Table 3) displayed on an exponential time scale. Immediately after light exposure, all retinas show massive stress signals, but by pLX 120 these are no longer evident. Müller cell seals form rapidly after light exposure and persist. Breakdown of the seal can be detected by pLX 14 and increases with time. Classic remodeling phenomena such as migration and microneuromas are evident by pLX60 but decline after emigration and retinal decimation become dominant.
Mentions: Environmental or inherited insults that kill photoreceptors are sensory deafferentations with the potential to trigger neural remodeling including neuronal loss, growth of new neurites, formation of new synapses, and even somatic migration. LIRD is a fast, effective trigger of large-scale remodeling (perhaps due to the high temporal coherence of the insult) that replicates and then progresses past phase III remodeling to ultimately decimate the neural retina (Figure 19). LIRD will enable detailed study of circuitry defects emergent from remodeling [5,6]. Moreover, the LIRD model presents derangements of cellular functions ranging from energetics (aspartate stress), osmoregulation (taurine dysregulation), retinoid processing (CRALBP expression fluctuations), global protein translation modulation (arginine upregulation), to glioma-like changes in glutamine metabolism. Collectively, these data demonstrate that LIRD models exhibit pathological processes observed in other retinal degenerative diseases and a variety of general neurodegenerations and neoplastic transformations. The LIRD model is a highly practical model for mimicking degenerative retinal disease without complicating developmental side-effects. Finally, the LIRD model is the only available model exhibiting all of the hallmarks of AMD including choroidal ablation, RPE ablation, photoreceptor cell death and retinal decimation.

Bottom Line: Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions.Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

View Article: PubMed Central - PubMed

Affiliation: Ophthalmology, University of Utah, John A. Moran Eye Center, Salt Lake City, UT 84132, USA. robert.marc@hsc.utah.edu

ABSTRACT

Purpose: Our objective was to comprehensively assess the nature and chronology of neural remodeling in retinal degenerations triggered by light-induced retinal damage (LIRD) in adult albino rodents. Our primary hypothesis is that all complete photoreceptor degenerations devolve to extensive remodeling. An hypothesis emergent from data analysis is that the LIRD model closely mimics late-stage atrophic age relared macular degeneration (AMD).

Methods: Sprague-Dawley (SD) rats received intense light exposures of varied durations and survival times ranging from 0 to 240 days. Remodeling was visualized by computational molecular phenotyping (CMP) of a small molecule library: 4-aminobutyrate (gamma), arginine (R), aspartate (D), glutamate (E), glutamine (Q), glutathione (J), glycine (G), and taurine (tau). This library was augmented by probes for key proteins such as rod opsin, cone opsin and cellular retinal binding protein (CRALBP). Quantitative CMP was used to profile 160 eyes from 86 animals in over 6,000 sections.

Results: The onset of remodeling in LIRD retinas is rapid, with immediate signs of metabolic stress in photoreceptors, the retinal pigmented epithelium (RPE), the choriocapillaris, and Müller cells. In particular, anomalous elevated aspartate levels appear to be an early stress marker in photoreceptors. After the stress phase, LIRD progresses to focal photoreceptor degeneration within 14 days and extensive remodeling by 60 days. RPE and choriocapillaris losses parallel Müller cell distal seal formation, with progressive neuronal migration, microneuroma evolution, fluid channel formation, and slow neuronal death. The remaining retina in advanced light damage can be classified as survivor, light damage (LD), or decimated zones where massive Müller cell and neuronal emigration into the choroid leaves a retina depleted of neurons and Müller cells. These zones and their transitions closely resemble human geographic atrophy. Across these zones, Müller cells manifest extreme changes in the definitive Müller cell tauQE signature, as well as CRALBP and arginine signals.

Conclusions: LIRD retinas manifest remodeling patterns of genetic retinal degeneration models, but involve no developmental complexities, and are ultimately more aggressive, devastating the remaining neural retina. The decimation of the neural retina via cell emigration through the perforated retina-choroid interface is a serious denouement. If focal remodeling in LIRD accurately profiles late stage atrophic age-related macular degenerations, it augurs poorly for simple molecular interventions. Indeed, the LIRD profile in the SD rat manifests more similarities to advanced human atrophic AMD than most genetically or immunologically induced murine models of AMD.

Show MeSH
Related in: MedlinePlus