Retinal Remodeling: Circuitry Revisions Triggered by Photoreceptor Degeneration

Abstract We report isolating the Drosophila retinal degeneration E (rdgE) mutation. The hypomorphic rdgE 1 allele causes rapid photoreceptor degeneration in light and a slower rate of degeneration when the flies are raised in constant darkness. The rdgE 1 flies exhibited an electrophysiological light response that decreased with age, coinciding with the degeneration. This suggests that degeneration caused the loss of the light response. We determined that the ninaE (rhodopsin) mutation, but not norpA [phospholipase C (PLC)], slowed the rdgE-dependent degeneration. This was consistent with the light-enhanced degeneration, but revealed that the degeneration is independent of the PLC-mediated phototransduction cascade. Transmission electron microscopy revealed that rdgE 1 photoreceptors exhibited a number of vesicular transport defects including unpacking/vesiculation of rhabdomeres, endocytosis of novel vesicles by photoreceptors, a buildup of very large multivesicular bodies, and an increased amount of rough endoplasmic reticulum. We determined that the rdgE null phenotype is a late embryonic lethality. Therefore, rdgE + is required in cells outside of the retina, quite possibly in a large number of neurons. Thus, rdgE may define a mutational class that exhibits both light-enhanced retinal degeneration and a recessive null lethality by perturbing neuronal membrane biosynthesis and/or recycling.

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The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

International Journal of Molecular Sciences ◽

10.3390/ijms22010052 ◽

2020 ◽

Vol 22 (1) ◽

pp. 52

Author(s):

Mirja Koch ◽

Constanze Scheel ◽

Hongwei Ma ◽

Fan Yang ◽

Michael Stadlmeier ◽

...

Keyword(s):

Protein Kinase ◽

Mouse Model ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Cone Photoreceptor ◽

Photoreceptor Degeneration ◽

Dependent Protein Kinase ◽

Genetic Ablation ◽

Cgmp Dependent Protein Kinase ◽

Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

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The Application of Methylprednisolone Nanoscale Zirconium-Porphyrin Metal-Organic Framework (MPS-NPMOF) in the Treatment of Photoreceptor Degeneration

International Journal of Nanomedicine ◽

10.2147/ijn.s225992 ◽

2019 ◽

Vol Volume 14 ◽

pp. 9763-9776

Author(s):

Yajie Wang ◽

Wei Liu ◽

Bo Yuan ◽

Xuebo Yin ◽

Yiming Li ◽

...

Keyword(s):

Metal Organic Framework ◽

Photoreceptor Degeneration ◽

Metal Organic ◽

Organic Framework

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The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Genes ◽

10.3390/genes10060453 ◽

2019 ◽

Vol 10 (6) ◽

pp. 453 ◽

Cited By ~ 8

Author(s):

Arianna Tolone ◽

Soumaya Belhadj ◽

Andreas Rentsch ◽

Frank Schwede ◽

François Paquet-Durand

Keyword(s):

Cell Death ◽

Gene Mutations ◽

Interdisciplinary Cooperation ◽

Response To Treatment ◽

Common Denominator ◽

Photoreceptor Degeneration ◽

Diverse Range ◽

Cell Death Pathway ◽

Cgmp Signaling ◽

Dependent Cell

Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

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Involvement of NT3 and P75NTR in photoreceptor degeneration following selective Müller cell ablation

Journal of Neuroinflammation ◽

10.1186/1742-2094-10-137 ◽

2013 ◽

Vol 10 (1) ◽

pp. 137 ◽

Cited By ~ 24

Author(s):

Weiyong Shen ◽

Ling Zhu ◽

So-Ra Lee ◽

Sook H Chung ◽

Mark C Gillies

Keyword(s):

Müller Cell ◽

Photoreceptor Degeneration ◽

Cell Ablation ◽

Muller Cell

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cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function

Journal of Neuroscience ◽

10.1523/jneurosci.0909-13.2013 ◽

2013 ◽

Vol 33 (37) ◽

pp. 14939-14948 ◽

Cited By ~ 35

Author(s):

J. Xu ◽

L. Morris ◽

A. Thapa ◽

H. Ma ◽

S. Michalakis ◽

...

Keyword(s):

Photoreceptor Degeneration ◽

Channel Function ◽

Cng Channel

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Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival

Nature Communications ◽

10.1038/ncomms7228 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 42

Author(s):

Dennis S. Rice ◽

Jorgelina M. Calandria ◽

William C. Gordon ◽

Bokkyoo Jun ◽

Yongdong Zhou ◽

...

Keyword(s):

Docosahexaenoic Acid ◽

Opposite Effect ◽

Photoreceptor Cell ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Adiponectin Receptor ◽

Cell Integrity ◽

Photoreceptor Degeneration ◽

Adiponectin Receptor 1

Abstract The identification of pathways necessary for photoreceptor and retinal pigment epithelium (RPE) function is critical to uncover therapies for blindness. Here we report the discovery of adiponectin receptor 1 (AdipoR1) as a regulator of these cells’ functions. Docosahexaenoic acid (DHA) is avidly retained in photoreceptors, while mechanisms controlling DHA uptake and retention are unknown. Thus, we demonstrate that AdipoR1 ablation results in DHA reduction. In situ hybridization reveals photoreceptor and RPE cell AdipoR1 expression, blunted in AdipoR1−/− mice. We also find decreased photoreceptor-specific phosphatidylcholine containing very long-chain polyunsaturated fatty acids and severely attenuated electroretinograms. These changes precede progressive photoreceptor degeneration in AdipoR1−/− mice. RPE-rich eyecup cultures from AdipoR1−/− reveal impaired DHA uptake. AdipoR1 overexpression in RPE cells enhances DHA uptake, whereas AdipoR1 silencing has the opposite effect. These results establish AdipoR1 as a regulatory switch of DHA uptake, retention, conservation and elongation in photoreceptors and RPE, thus preserving photoreceptor cell integrity.

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