Longitudinal Study of Cone Photoreceptors during Retinal Degeneration and in Response to Ciliary Neurotrophic Factor Treatment

Talcott, Katherine E.; Ratnam, Kavitha; Sundquist, S.; Lucero, Anna S.; Lujan, Brandon J.; Tao, Wenjing; Porco, Travis C.; Roorda, Austin; Duncan, Jacque L.

doi:10.1167/iovs.10-6479

Cited by 255 publications

(234 citation statements)

References 27 publications

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“…3 Neuroprotection strategies targeting apoptotic rod cell death in animal models have proved effective, 52 although such strategies have yet to be translated into effective clinical treatments. 53 This may be in part due to the observation that if the caspase-dependent cell death pathway is blocked then necroptosis is activated as a second line of defense. 11,54 Less is known regarding cone cell death, however, loss of rod-derived growth factors, autophagy and oxidative stress are key contributors.…”

Section: Discussionmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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Section: Discussionmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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“…(http://www.neurotechusa.com/news_events/pr_2007-04-17.asp). 39 Another cone cell survival factor showing substantial promise in slowing retinal degeneration is rod-derived cone viability factor. This protein is a member of the thioredoxin family, and has been shown to be protective against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

et al. 2011

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Retinitis pigmentosa (RP) is a degenerative retinal disease involving progressive loss of rod and cone photoreceptor function. It represents the most common form of registered blindness among the working aged populations of developed countries. Given the immense genetic heterogeneity associated with this disease, parameters influencing cone photoreceptor survival (preservation of daytime vision) that are independent of primary mutations are exceedingly important to identify from a therapeutic standpoint. Here we identify C1q, the primary component of the classical complement pathway, as a cone photoreceptor neuronal survival factor. European Journal of Human Genetics (2012) 20, 64-68; doi:10.1038/ejhg.2011; published online 24 August 2011Keywords: C1qa; C3; retinopathy; retinitis pigmentosa; complement; cone photoreceptors INTRODUCTION Hereditary retinopathies, prominent among which is retinitis pigmentosa (RP), conditions involving progressive death of photoreceptors are amongst the most genetically heterogeneous of any group of mendelian conditions. Including Leber's congenital amaurosis (LCA), a congenital retinopathy with pathological features bearing similarities to RP, 60 genes have now been implicated in disease etiology. If syndromic forms of disease and other hereditary retinopathies are included, 202 genetic loci have been identified and a total of 161 genes so far characterized. 1 RP segregates largely in an autosomal dominant, recessive, or X-linked recessive manner, 2 whereas all of the 16 genetic forms of LCA that have been identified to date are autosomal recessive; hence, gene therapies require strategies based either on gene replacement, or on the selective suppression of dominantly mutated genes, or their transcripts. Progress is being made to the extent that clinical trials involving AAV-mediated gene replacement have now been established for one form of LCA caused by mutations within the RPE65 gene. [3][4][5] In addition, therapeutic modalities have been demonstrated for other genetic subtypes of RP and LCA in a growing number of animal models, both of recessive and dominant forms of disease. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Notwithstanding such progress, the genetic complexity of this group of diseases represents a formidable logistic and economic hurdle in developing viable methods of prevention. Given this caveat, parameters effecting photoreceptor survival that are independent of the primary genetic lesion are critically important to identify. It has emerged over the last 5 or so years that major pathological features involving sub-retinal drusen deposition and choroidal neovascularization that are associated with one form of multifactorial retinopathy, namely age-related macular degeneration, where the central cone-rich part of the retina, or macula, degenerates, can now be explained, at least in part, by excessive complement activity on ocular surfaces. [24][25][26][27][28][29][30] However, the influence of complement on cone photoreceptor survival is...

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“…AO scanning light ophthalmoscopy (AOSLO) (12) has been used to investigate how our visual capabilities are formed from discrete sampling by individual cones (13,14), and how disease alters the living retina at a cellular level (15)(16)(17)(18). AOSLO has proven to be a powerful platform for translating existing microscopy and ophthalmoscopy methods for high-resolution in vivo imaging.…”

mentioning

confidence: 99%

Imaging individual neurons in the retinal ganglion cell layer of the living eye

Rossi

Granger

Sharma

et al. 2017

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

178

151

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Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain.

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Longitudinal Study of Cone Photoreceptors during Retinal Degeneration and in Response to Ciliary Neurotrophic Factor Treatment

Cited by 255 publications

References 27 publications

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

Imaging individual neurons in the retinal ganglion cell layer of the living eye

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