Neuroprotective Strategy in Retinal Degeneration: Suppressing ER Stress-Induced Cell Death via Inhibition of the mTOR Signal

Abstract

The retina is a specialized sensory organ, which is essential for light detection and visual formation in the human eye. Inherited retinal degenerations are a heterogeneous group of eye diseases that can eventually cause permanent vision loss. UPR (unfolded protein response) and ER (endoplasmic reticulum) stress plays an important role in the pathological mechanism of retinal degenerative diseases. mTOR (the mammalian target of rapamycin) kinase, as a signaling hub, controls many cellular processes, covering protein synthesis, RNA translation, ER stress, and apoptosis. Here, the hypothesis that inhibition of mTOR signaling suppresses ER stress-induced cell death in retinal degenerative disorders is discussed. This review surveys knowledge of the influence of mTOR signaling on ER stress arising from misfolded proteins and genetic mutations in retinal degenerative diseases and highlights potential neuroprotective strategies for treatment and therapeutic implications.

Keywords: ER stress; apoptosis; mTOR; retinal degeneration; retinal neuroprotection; unfolded protein response.

Figure 1

The unfolded protein response (UPR).There are three known pathways triggering UPR in ER. (i) PERK (protein kinase RNA-like ER kinase) phosphorylates initiation factor eIF2α, leading to cap independent translation of ATF4 (activating transcription factor 4). ATF4 activates CHOP (C/EBP homologous protein), which can stimulate apoptosis; (ii) IRE1 (inositol-requiring protein 1), is a kinase that leads to activation of RNAse activity. This induces the splicing of XBP1 mRNA and further activates ERAD (ER-associated protein degradation); (iii) following BiP (Immunoglobulin binding protein) dissociation, ATF6 is cleaved by the S1P and S2P proteases into an active form in the Golgi. The activated ATF6 will then cause the activation of ERAD to restore ER (endoplasmic reticulum) homeostasis.

Figure 2

Schematic representation of the mTOR signaling pathway. mTORC1 is activated by Rheb (Ras homolog enriched in brain); the two most well-known downstream targets of mTORC1 are S6K1 (S6 kinase 1) and 4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1). As an upstream signal, TSC (tuberous sclerosis complex) can suppress Rheb to negatively regulate mTORC1. Furthermore, PTEN (phosphatase and tensin homolog deleted on chromosome 10) can be suppressed by PI3K (phosphoinositide 3-kinase), thus inactivating the mTOR pathway. In addition, AMPK (AMP-dependent kinase) is activated by a high AMP/ATP ratio and suppresses mTOR. The main function of mTORC1 activity is the stimulation of mRNA translation, protein synthesis, and autophagy inhibition. PIP2/PIP3, Phosphatidylinositol 4,5-bisphosphate/Phosphatidylinositol 3,4,5-triphosphate; PDK1, 3-Phosphoinositide-dependent protein kinase 1; AKT1, AKT serine/threonine kinase 1; PRAS40, 40 kDa pro-rich AKT1 substrate 1; RAPTOR, regulatory associated protein of mTOR; mLST8, mammalian lethal with SEC13 protein 8; DEPTOR, DEP domain-containing mTOR-interacting protein.

Figure 3

Inhibition of the mTOR signal suppresses ER stress-induced cell death. Inhibition of mTOR maintains cellular proteostasis and attenuates ER stress by reducing misfolded protein synthesis. In addition, inhibition of mTOR can augment autophagy to remove misfolded proteins generated from mutant genes. mTOR inhibition can suppress ER stress-induced apoptosis by regulating retina protein biosynthesis and degradation.