Journal
PROGRESS IN RETINAL AND EYE RESEARCH
Volume 79, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.preteyeres.2020.100860
Keywords
Unfolded protein response; Retinal degeneration; Translation; Translational repressor; Neuroprotection
Categories
Funding
- National Eye Institute [RO1 EY027763, P30 EY003039]
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Physiological equilibrium in the retina depends on coordinated work between rod and cone photoreceptors and can be compromised by the expression of mutant proteins leading to inherited retinal degeneration (IRD). IRD is a diverse group of retinal dystrophies with multifaceted molecular mechanisms that are not fully understood. In this review, we focus on the contribution of chronically activated unfolded protein response (UPR) to inherited retinal pathogenesis, placing special emphasis on studies employing genetically modified animal models. As constitutively active UPR in degenerating retinas may activate pro-apoptotic programs associated with oxidative stress, pro-inflammatory signaling, dysfunctional autophagy, free cytosolic Ca2+ overload, and altered protein synthesis rate in the retina, we focus on the regulatory mechanisms of translational attenuation and approaches to overcoming translational attenuation in degenerating retinas. We also discuss current research on the role of the UPR mediator PERK and its downstream targets in degenerating retinas and highlight the therapeutic benefits of reprogramming PERK signaling in preclinical animal models of IRD. Finally, we describe pharmacological approaches targeting UPR in ocular diseases and consider their potential applications to IRD.
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