Necrotic cone photoreceptor cell death in retinitis pigmentosa

Murakami, Yusuke; Ikeda, Yasuhiro; Nakatake, Shunji; Miller, J W; Vavvas, Demetrios G.; Sonoda, Koh Hei; Ishibashi, Tatsuro

doi:10.1038/cddis.2015.385

Cited by 21 publications

(17 citation statements)

References 12 publications

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“…However, we did not observe OKR in zebrafish gosh or els (pde6c rw76a ) mutant embryos injected with morpholino antisense of rip3 (data not shown). Furthermore, it was reported that cone cell death in zebrafish pde6c w59 mutants is induced cell-autonomously30, in contrast to the cell-non-autonomous necroptotic cone cell death model31. Further investigation is required to understand cell death mechanisms in zebrafish aipl1b and pde6c mutants.…”

Section: Discussionmentioning

confidence: 99%

Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Iribarne

Nishiwaki

Nakamura

et al. 2017

Sci Rep

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Genetic mutations in aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) cause photoreceptor degeneration associated with Leber congenital amaurosis 4 (LCA4) in human patients. Here we report retinal phenotypes of a zebrafish aipl1 mutant, gold rush (gosh). In zebrafish, there are two aipl1 genes, aipl1a and aipl1b, which are expressed mainly in rods and cones, respectively. The gosh mutant gene encodes cone-specific aipl1, aipl1b. Cone photoreceptors undergo progressive degeneration in the gosh mutant, indicating that aipl1b is required for cone survival. Furthermore, the cone-specific subunit of cGMP phosphodiesterase 6 (Pde6c) is markedly decreased in the gosh mutant, and the gosh mutation genetically interacts with zebrafish pde6c mutation eclipse (els). These data suggest that Aipl1 is required for Pde6c stability and function. In addition to Pde6c, we found that zebrafish cone-specific guanylate cyclase, zGc3, is also decreased in the gosh and els mutants. Furthermore, zGc3 knockdown embryos showed a marked reduction in Pde6c. These observations illustrate the interdependence of cGMP metabolism regulators between Aipl1, Pde6c, and Gc3 in photoreceptors.

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Section: Discussionmentioning

confidence: 99%

Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Iribarne

Nishiwaki

Nakamura

et al. 2017

Sci Rep

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“…In retinal degenerative disease (RD), numerous single-gene mutations in rod photoreceptors not only lead to rod pathology, but are also harmful to their cellular neighbors (8)(9)(10). For example, cones, which are critical for everyday activities, such as discriminating colors, reading, driving, and recognizing faces, do not express defective rod proteins, but they degenerate after rods are lost (11)(12)(13). The secondary loss of cones in RD is the major cause of blindness and disability, and its cause is a subject of intense investigation.…”

Section: Introductionmentioning

confidence: 99%

Blood-retina barrier failure and vision loss in neuron-specific degeneration

Ivanova¹,

Alam²,

Prusky³

et al. 2019

JCI Insight

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“…One possible contributor to nonautonomous cone degeneration in RP that has yet to be closely examined is the body's own immune system. As they die, many cells, including photoreceptors in RP, release damage-associated molecular patterns (DAMPs) that act as endogenous danger signals and incite inflammation (17,18). By numerous pathways, DAMPs can then stimulate proinflammatory cytokine activity or recruit immune cells, such as neutrophils and T cells, to the site of cell death (17).…”

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confidence: 99%

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

Wang

Xue

Rana

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is a disease that initially presents as night blindness due to genetic deficits in the rod photoreceptors of the retina. Rods then die, causing dysfunction and death of cone photoreceptors, the cell type that mediates high acuity and color vision, ultimately leading to blindness. We investigated immune responses in mouse models of RP and found evidence of microglia activation throughout the period of cone degeneration. Using adeno-associated vectors (AAVs), delivery of genes encoding microglial regulatory signals led to the identification of AAV serotype 8 (AAV8) soluble CX3CL1 (sCX3CL1) as a promising therapy for degenerating cones. Subretinal injection of AAV8-sCX3CL1 significantly prolonged cone survival in three strains of RP mice. Rescue of cones was accompanied by improvements in visual function. AAV8-sCX3CL1 did not affect rod survival, microglia localization, or inflammatory cytokine levels in the retina. Furthermore, although RNA sequencing of microglia demonstrated marked transcriptional changes with AAV8-sCX3CL1, pharmacological depletion of up to ∼99% of microglia failed to abrogate the effect of AAV8-sCX3CL1 on cone survival. These findings indicate that AAV8-sCX3CL1 can rescue cones in multiple mouse models of RP via a pathway that does not require normal numbers of microglia. Gene therapy with sCX3CL1 is a promising mutation-independent approach to preserve vision in RP and potentially other forms of retinal degeneration. retinitis pigmentosa | cone degeneration | gene therapy | CX3CL1 | microglia

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Necrotic cone photoreceptor cell death in retinitis pigmentosa

Cited by 21 publications

References 12 publications

Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Blood-retina barrier failure and vision loss in neuron-specific degeneration

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

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