Defective photoreceptor phagocytosis in a mouse model of enhanced S‐cone syndrome causes progressive retinal degeneration

Mustafi, Debarshi; Kevany, Brian M.; Genoud, Christel; Okano, Kiichiro; Cideciyan, Artur V.; Sumaroka, Alexander; Román, Alejandro J.; Jacobson, Samuel G.; Engel, Andréas; Adams, Mark D.; Palczewski, Krzysztof

doi:10.1096/fj.11-186767

Cited by 75 publications

(104 citation statements)

References 91 publications

(154 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…RNA-Seq results have been shown to correlate strongly with RT-PCR findings in the eye and retinal tissues (17,18), and this was further demonstrated with a cohort of RT-PCR probes (Supplemental Figure 6, A and B). The RNASeq data were further validated for visual cycle proteins by immunoblotting (Supplemental Figure 6C).…”

Section: Figurementioning

confidence: 53%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age-related disorders, but their complex etiology is poorly understood. Postmitotic neurons, such as photoreceptor cells in the retina and epithelial cells in the adjacent retinal pigmented epithelium, are especially susceptible to cellular senescence, which contributes to age-related retinal degeneration (ARD). The multigenic and complex etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the genetic differences that drive ARD pathogenesis, we studied A/J mice, which develop ARD more pronounced than that in other inbred mouse models. Although our investigation of consomic strains failed to identify a chromosome associated with the observed retinal deterioration, pathway analysis of RNA-Seq data from young mice prior to retinal pathological changes revealed that increased vulnerability to ARD in A/J mice was due to initially high levels of inflammatory factors and low levels of homeostatic neuroprotective factors. The genetic signatures of an uncompensated preinflammatory state and ARD progression identified here aid in understanding the susceptible genetic loci that underlie pathogenic mechanisms of age-associated disorders, including several human blinding diseases. IntroductionAge-related disorders arise from failure of tissue maintenance and repair pathways that are accelerated by certain inherited and acquired factors (1). Long-lived nondividing cells, such as neurons, have markedly reduced tolerance to damage (2), and thus exhibit the most pronounced age-related changes. Neuronal cells in the retina are an especially attractive model system to study this phenomenon, owing to their accessibility and wellunderstood physiology. Rod and cone photoreceptors are retinal neuronal cells that initiate visual perception, a function requiring a competent neighboring retinal pigmented epithelium (RPE) for their normal operation (3). In postmitotic cells such as these photoreceptor and RPE cells, cellular senescence can ensue when shed oxidized photoreceptor outer segments (POS) are inadequately phagocytosed and digested by the RPE. This results in accumulation of damaged proteins, formation of toxic metabolic byproducts, inflammatory cell invasion, and cell death. RPE cells are the most affected because, in addition to processing POS, they serve as the conduit between photoreceptors and the choroidal blood supply for metabolite exchange (4). Acquisition of senescence-associated pathology stimulates cells to secrete various factors that contribute to tissue dysfunction. Conversely, adequate clearance of such cells can delay the onset of age-related tissue pathology (5).Aging laboratory experimental animals are important models for studying age-related pathology, especially neurodegenerative disorders, which have been shown to be affected by their genetic backgrounds (6, 7). The A/J inbred mouse ...

show abstract

Section: Figurementioning

confidence: 53%

Inflammatory priming predisposes mice to age-related retinal degeneration

Mustafi¹,

Maeda²,

Kohno³

et al. 2012

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Eyes from 4-week-old C57BL/6J mice (The Jackson Laboratory) were enucleated and immediately processed to isolate total RNA that was used to prepare cDNA libraries for sequencing with the Illumina platform of RNA sequencing instruments (47,83). Three biological replicates were made for both whole-eye and retinal tissue to generate transcriptome data used to determine the FPKM for normalization and differential expression analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Eye and retinal tissue libraries were prepared as previously described (47,83). Each mouse and human library was run on the Illumina Genome Analyzer IIx (Illumina) in the CWRU Genomics core facility using 36-79 single-end read lengths.…”

Section: Methodsmentioning

confidence: 99%

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

et al. 2013

Self Cite

View full text Add to dashboard Cite

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.

show abstract

“…These structural defects could have profound effects not only on the photoreceptors, but also on the RPE layer, which must clear these aberrant discs by phagocytosis. Therefore, to understand the effect of E150K mutant rhodopsin, we imaged the photoreceptor-RPE interface with serial block face scanning electron microscopy (SBF-SEM) of P14 KK mice (36,37). A 15-μm-thick section of KK mouse retina outside of the optic nerve was sectioned 100 nm at a time.…”

Section: Figurementioning

confidence: 99%

“…Blocks prepared for TEM were used for SBF-SEM. The sample was prepared and cut using a Quanta 200 (FEI) with Gatan 3View software as described previously (37). Serial sectioning was performed on the block face by cutting a 100-nm slice from the face with a diamond knife and imaging the freshly cut block from the backscattered electron signal.…”

Section: Figure 10mentioning

confidence: 99%

Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization

et al. 2012

Self Cite

View full text Add to dashboard Cite

The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higherorder organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.

show abstract

Defective photoreceptor phagocytosis in a mouse model of enhanced S‐cone syndrome causes progressive retinal degeneration

Cited by 75 publications

References 91 publications

Inflammatory priming predisposes mice to age-related retinal degeneration

Inflammatory priming predisposes mice to age-related retinal degeneration

Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration

Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization

Contact Info

Product

Resources

About