As researchers begin to explore various treatment options for vision loss and blindness, one particular target currently under investigation is the c-Jun N-Terminal Kinase (JNK) pathway. Activation of this pathway is associated with the cellular death of a variety of retinal cells. Genetic and pharmacological inhibition of JNK signaling in a number of different models of retinal degeneration has shown promising results in reducing pathologic progression and protection against cellular death.
Retinal degenerative diseases are responsible for vision loss, including complete blindness, in millions of people worldwide. For many of these patients, performing basic functions like reading, driving or even watching TV becomes a challenge, resulting in a loss of personal independence.
The retina has 10 different cell layers, including retinal ganglion cells (RGC), photoreceptor rods and cones, and retinal pigment epithelial cells (RPE). A key aspect to the pathology of retinal degenerative diseases is the dysfunction and/or death of many of the cells that are involved in the complex process of vision whereby light waves, or photons, are converted into electrical signals in a process known as phototransduction. These electrical signals are then transmitted to the brain via the optic nerve, chiasm and tract. In order for us to better understand and develop improved methods for the prevention and treatment of visual loss, numerous studies have been directed at understanding the underlying molecular mechanisms of injury in the visual system.
A mini-review1 written by Byung- Jin Kim and Donald J. Zack published in Retinal Degenerative Diseases, Advances in Experimental Medicine and Biology discusses the impact of c-Jun N-terminal kinase (JNK) signaling in retinal disease, focusing on RGCs, RPEs, photoreceptor cells in animal studies, with particular attention to the modulation of JNK signaling as a potential therapeutic target for the treatment of retinal disease.
“JNK, a member of the stress-induced mitogen-activated protein (MAP) kinase family, has been shown to modulate a variety of biological processes associated with the neurodegenerative pathology of the retina. In particular, various retinal cell culture and animal models related to glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa indicate that JNK signaling may contribute to disease pathogenesis,” the authors reported.
Relation to Glaucoma and Other Diseases
As early as 1999, HA Quigley reported in Progress in Retinal and Eye Research2 that RGCs transmit visual information from the bipolar cells in the retina to vision relay centers in the brain, such as the lateral geniculate nucleus (LGN) and superior colliculus (SC), and ultimately to the visual cortex. Injury and death of RGCs, which together constitute the so-called optic neuropathies, are a major cause of vision loss and blindness worldwide.
In later years, various in vivo models of optic nerve disease like neuronal excitotoxicity by N-methyl-D-aspartate (NMDA), experimental optic nerve crush (ONC) and retinal ischemic injury have been actively investigated to study the impact of JNK and its upstream/downstream pathways in RGC death.
As an example, Fernandes et al. (Neurobiology Disease, 2012)3 demonstrated that combined deletion of the JNK2 and JNK3 genes inhibited RGC death with long-term protection after ONC injury, and a similar effect was shown by conditional deletion of JUN, a downstream signaling molecule of JNK. In addition to this, according to Welsbie et al. (Proceedings of the National Academy of Sciences of the United States of America, 2013)4, blockage of upstream signaling of JNK led to significantly decreased JNK activation that was associated with enhanced RGC survival following ONC.
Several studies also suggested that pharmacological inhibition of JNK activation could significantly increase RGC viability and prevent inner retinal degeneration. Kim et al. (Molecular Neurodegeneration, 2016)5 demonstrated that ischemia/reperfusion (I/R) triggered JNK activation in various cells in the inner retinal layers and RGC axonal loss was significantly inhibited by administration of SP600125. This finding suggested that activation of JNK plays a pivotal role in RGC death.
When taken together, the numerous findings mentioned in Byung-Jin Kim and Donald J. Zack’s paper1 indicated that JNK inhibitors may be an interesting class of pharmacological molecules for the promotion of RGC survival through the inhibition of JNK activation to prevent RGC death and simultaneously inhibit proinflammatory responses in glial cells.
Possible Relationship with Age-Related Macular Degeneration
The biology of RPE cells in human diseases has been actively investigated, particularly in age-related macular degeneration (AMD), as already reported by RW Young (Survey of Ophthalmology, 1987)6 two decades earlier. Today, the late stages of AMD, which is a leading cause of vision loss in the elderly in the United States and other developed Western countries, can be categorized into two broad types: non-neovascular (dry) or neovascular (wet). The non-neovascular form is more common, but the neovascular form is generally associated with more severe vision loss.
RPE cells constitutively produce VEGF, and produce more in response to pathologic conditions (Blaauwgeers et al., The American Journal of Pathology, 1999; Holtkamp et al., Progress in Retinal and Eye Research, 2001).7,8 Importantly, JNK has been suggested as a key signaling molecule promoting VEGF expression through phosphorylation of c-Jun and binding to the VEGF promotor, thereby mediating neovascularization (Du et al., Proceedings of the National Academy of Sciences of the United States of America, 2013; Guma et al., Proceedings of the National Academy of Sciences of the United States of America, 2009).9,10 Despite these studies, the role of JNK in RPE viability remains controversial.
Cao and colleagues (Molecular Medicine Reports, 2012)11 showed that ultraviolet B radiation induced apoptotic cell death of the ARPE-19 RPE cell line and surprisingly, inhibition of JNK exacerbated apoptosis, whereas activation of JNK attenuated ARPE-19 cell death, suggesting an anti-apoptotic role of JNK. In contrast, Roduit and Schorderet reported enhanced RPE cell survival upon JNK inhibition under UV irradiation (Apoptosis, 2008).12 This issue is not resolved and warrants further research.
JNK Signaling and Photoreceptor Degeneration
The association of JNK with photoreceptor cell death has been studied less than other retinal cell types. Nonetheless, several in vitro and animal models have suggested that JNK may mediate photoreceptor cell death, initiated by various genetic and environmental factors.
Using the photoreceptor cell line 661 W, Choudhury et al. (Cell Death & Disease, 2013)13 showed that reprogramming of the unfolded protein response (UPR) by genetic deletion of caspase 7 resulted in a decrease of JNK-induced apoptosis. This finding suggests that JNK is an important apoptotic mediator of UPR, which is known as a major causative process of photoreceptor cell death in some forms of retinitis pigmentosa (Galy et al., Human Molecular Genetics, 2005; Kang et al., Nature Cell Biology, 2012).14,15 These findings indicate that JNK may play an important role in photoreceptor cell death as well.
JNK Signaling Pathway: A Potential Therapeutic Target in Retinal Degenerative Disease?
In summary, Byung-Jin Kim and Donald J. Zack’s mini-review1 indicates that apoptosis of a variety of retinal cells is associated with the activation of the JNK pathway. In addition, genetic and pharmacological inhibition of JNK signaling resulted in protection from cell death and reduced pathologic progression in a number of different models of retinal degeneration.
As a common mediator of retinal cell death, the pharmacological inhibition of JNK, or associated family members, may provide a pathway for a “generic” treatment strategy that is relatively independent of the specific genetic mutation causing the disease.
JNK inhibition strategies may also provide a complementary treatment approach to gene-specific therapies.
“For these reasons, it seems reasonable to pursue the JNK pathway as a promising target for the development of novel therapeutic strategies for treatment of the photoreceptor degenerative diseases,” concluded Byung-Jin Kim and Donald J. Zack.
References:
1 Kim BJ, Zack DJ. The Role of c-Jun N-Terminal Kinase (JNK) in Retinal Degeneration and Vision Loss. Adv Exp Med Biol. 2018;1074:351-357.
2 Quigley HA. Neuronal death in glaucoma. Prog Retin Eye Res. 1999;18(1):39–57.
3 Fernandes KA, Harder JM, Fornarola LB, et al. JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death. Neurobiol Dis. 2012;46(2):393–401.
4 Welsbie DS, Yang Z, Ge Y, et al. Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death. Proc Natl Acad Sci U S A. 2013;110(10):4045–4050.
5 Kim BJ, Silverman SM, Liu Y, et al. In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells. Mol Neurodegener. 2016;11:30.
6 Young RW. Pathophysiology of age-related macular degeneration. Surv Ophthalmol. 1987;31(5):291–306.
7 Blaauwgeers HG, Holtkamp GM, Rutten H, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol. 1999;155(2):421–428.
8 Holtkamp GM, Kijlstra A, Peek R, et al. Retinal pigment epithelium-immune system interactions: cytokine production and cytokine-induced changes. Prog Retin Eye Res. 2001;20:29–48.
9 Du H, Sun X, Guma M, et al. JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci U S A. 2013;110(6):2377–2382.
10 Guma M, Rius J, Duong-Polk KX, et al. Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression. Proc Natl Acad Sci U S A. 2009;106(21):8760–8765.
11 Cao G, Chen M, Song Q, et al. EGCG protects against UVB-induced apoptosis via oxidative stress and the JNK1/c-Jun pathway in ARPE19 cells. Mol Med Rep.2012;5(1):54–59.
12 Roduit R, Schorderet DF. MAP kinase pathways in UV-induced apoptosis of retinal pigment epithelium ARPE19 cells. Apoptosis. 2008;13(3):343–353.
13 Choudhury S, Bhootada Y, Gorbatyuk O, et al. Caspase-7 ablation modulates UPR, reprograms TRAF2-JNK apoptosis and protects T17M rhodopsin mice from severe retinal degeneration. Cell Death Dis. 2013;4:e528.
14 Galy A, Roux MJ, Sahel JA, et al. Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for RhodopsinPro23His human retinitis pigmentosa. Hum Mol Genet. 2005;14(17):2547–2557.15 Kang MJ, Chung J, Ryoo HD. CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Nat Cell Biol. 2012;14(4):409–415.
