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. Author manuscript; available in PMC: 2017 Oct 1.
Published in final edited form as: Brain Res. 2016 Apr 23;1648(Pt B):538–541. doi: 10.1016/j.brainres.2016.04.021

Endoplasmic Reticulum Stress in Human Photoreceptor Diseases

Priscilla Chan 1, Julia Stolz 2, Susanne Kohl 2, Wei-Chieh Chiang 1, Jonathan H Lin 1
PMCID: PMC5036988  NIHMSID: NIHMS782796  PMID: 27117871

Abstract

Photoreceptors are specialized sensory neurons essential for light detection in the human eye. Photoreceptor cell dysfunction and death cause vision loss in many eye diseases such as retinitis pigmentosa and achromatopsia. Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling have been implicated in the development and pathology of heritable forms of retinitis pigmentosa and achromatopsia. We review the role of ER stress and UPR in retinitis pigmentosa arising from misfolded rhodopsins (RHO) and in achromatopsia arising from genetic mutations in Activating Transcription Factor 6 (ATF6).

Keywords: Photoreceptor, Retinitis pigmentosa, Achromatopsia rhodopsin, ATF6, retina

1. Introduction

1.1. Retina, rods, and cones

The human retina lines the posterior concavity of the eye and is dedicated to sensing, processing, and sending visual information collected from the environment to the brain. Photoreceptors are specialized sensory neurons in the outer nuclear layer of the retina that detect light and activate retinal circuitry. Two types of photoreceptors, rods and cones, are found in vertebrates including man (Sung and Chuang, 2010). Rod photoreceptors have slender, rod-shaped, modified cilia, termed outer segments, and comprise the majority of photoreceptors in the retina. Rods are activated by low intensities of light and are responsible for vision under dim and nocturnal conditions. By contrast, cone photoreceptors have a conical outer segment and are much less common than rods but – in humans – are highly enriched in the macula region of the retina, our point of highest visual acuity and special resolution. Cones are activated by higher intensities of light and mediate diurnal and color vision, the latter by subspecialization into different wavelength sensitivities. Many human blinding diseases arise when rods and/or cones are damaged or dysfunctional.

Photoreceptors produce unique proteins to transduce photonic stimuli into electrical signals and to maintain their structural integrity and lamination in the neuroretina (Sung and Chuang, 2010). Photoreceptors turn over many of these proteins through a daily process involving “shedding” of their outer segment tips to remove damaged proteins as well as to enable neighboring retinal pigment epithelial cells to recycle essential nutrients back to the photoreceptors (Sung and Chuang, 2010). Photoreceptors expend significant amounts of energy to perform these essential biosynthetic tasks and are metabolically the most active cells in the human body (Sung and Chuang, 2010; Wong-Riley, 2010).

1.2 Endoplasmic reticulum organelle

The endoplasmic reticulum (ER) is an organelle dedicated to biosynthesis, folding, and assembly of membrane and secreted proteins, lipid and sterol metabolism, and free calcium storage (Alberts, 2008). Pathologic and environmental conditions that disrupt ER functions lead to ER stress (Hetz and Mollereau, 2014; Hiramatsu et al., 2015; Wang and Kaufman, 2016). To alleviate ER stress, cells activate the Unfolded Protein Response (UPR) (Walter and Ron, 2011; Wang and Kaufman, 2016). In mammals, the UPR is controlled by three ER resident transmembrane proteins: IRE1, PERK, and ATF6 (Walter and Ron, 2011; Wang and Kaufman, 2016). When activated by ER stress, IRE1, PERK, and ATF6 initiate intracellular signal transduction pathways that turn on transcriptional programs that enhance ER function by increasing ER size, increasing ER protein folding enzymes and chaperones, and increasing degradation of damaged proteins. PERK signaling also attenuates ribosome assembly on mRNAs so that protein translation is decreased. By reducing the metabolic demand of protein folding and enhancing the functional capacity of the ER, the UPR enables cells to adjust to and survive periods of ER stress. If ER stress persists despite these actions, UPR signaling “switches” to promote cell death by activating the intrinsic apoptosis machinery.

ER stress and UPR signaling are molecular pathologic mechanisms found in a wide variety of eye diseases (Kroeger et al., 2014; Zhang et al., 2014; Zhang et al., 2015; Zode et al., 2011). Here, we review the role of ER stress and UPR in the development of two photoreceptor diseases: retinitis pigmentosa and achromatopsia.

2. ER Stress in Retinitis Pigmentosa

Retinitis pigmentosa is a retinal degenerative disease that affects an estimated 1.5 million people worldwide (Berson, 1993). Clinically, the disease is characterized by night blindness and loss of peripheral vision due to degeneration of the rod photoreceptors that progressively worsens to damage central vision over the course of years by a secondary loss of the cone photoreceptors (Berson, 1993). Retinitis pigmentosa is a genetically heterogeneous disease with autosomal dominant, autosomal recessive, and X-linked subtypes (Dryja and Li, 1995). Mutations in rhodopsin (RHO) are a common genetic cause of autosomal dominantly inherited retinitis pigmentosa, and these patients experience progressive loss of rod photoreceptors which will eventually also lead to loss of cones (Dryja et al., 1990; Dryja, 1992).

Rhodopsin (RHO) is a small 348 amino acid, G-protein-coupled transmembrane receptor protein exclusively expressed by rods (Palczewski, 2006). When covalently linked to 11-cis-retinal, RHO responds to light to initiate the phototransduction cascade that generates electrical signals in the neuroretina (Palczewski, 2012). RHO is essential for photoreceptor function and survival, and RHO knockout mice (Rho−/−) develop retinal degeneration very early in life (Humphries et al., 1997). Almost 200 different RHO mutations have been found in retinitis pigmentosa patients. Many of these mutations introduce missense changes that cause the mutant RHO protein to misfold in the ER (Chiang et al., 2012; Chiang et al., 2014; Illing et al., 2002; Kaushal and Khorana, 1994; Sung et al., 1991).

The proline to histidine mutation at position 23 (P23H) of rhodopsin (RhoP23H) is the most common cause of heritable retinitis pigmentosa in North America accounting for 10% of adRP patients (Dryja et al., 1991; Dryja and Li, 1995). Mutant RhoP23H protein extensively aggregates in vitro and fails to traffic efficiently out of the ER in rod photoreceptors (Saliba et al., 2002). RhoP23H causes ER stress and activates UPR in transgenic animal models of retinitis pigmentosa prior to overt photoreceptor cell death (Kroeger et al., 2014; Lin et al., 2007). Most recently, a P23H rhodopsin knock-in mouse (RhoP23H/+) was created that closely recapitulated the spatial distribution and temporal progression of photoreceptor cell death and vision loss found in patients with the same mutation (Sakami et al., 2011). When (RhoP23H/+) were crossed with ER Stress-Activated Indicator (ERAI) mice, a transgenic reporter mouse line that produces fluorescent XBP1-Venus fusion protein when the IRE1 branch of the UPR is activated (Iwawaki et al., 2004), robust fluorescent signal was selectively seen in rod photoreceptors in RhoP23H/+ mice (Chiang et al., 2015). Consistent with increased reporter activity, levels of spliced Xbp-1 mRNA, XBP1 protein, and transcriptional targets of XBP1s were all significantly elevated in retinas of RhoP23H/+ mice (Chiang et al., 2015). Increased IRE1 signaling through XBP1 generation was observed prior to photoreceptor cell loss in RhoP23H/+ mice (Chiang et al., 2015). However, no activation of c-Jun N-terminal kinase, IRE1-dependent mRNA decay, or signaling via the PERK arm of the UPR was observed in RhoP23H/+ mice at these ages (Chiang et al., 2015). These findings demonstrate that RhoP23H causes ER stress in vivo in rods. Furthermore, the physiologic ER stress caused by RhoP23H activates a “partial” or “selective” UPR in photoreceptors of RhoP23H/+ mice that is dominated by IRE1’s generation of XBP1. By contrast, pharmacologic ER stress caused by tunicamycin or thapsigargin activates all UPR signaling pathways simultaneously.

What is the function of XBP1 generation in photoreceptors of RhoP23H/+ mice? Many of XBP1’ target genes, including those found to be upregulated in the retinas of RhoP23H/+ mice, encode components of the ER-associated protein degradation (ERAD) machinery (Chiang et al., 2015; Lee et al., 2003; Shoulders et al., 2013). P23H rhodopsin’s propensity to misfold in the ER and its robust production makes it a prime target for ERAD in photoreceptors. Indeed, RhoP23H was found to be heavily ubiquitinated when immunoprecipitated from photoreceptors of RhoP23H/+ mice (Chiang et al., 2015). Furthermore, miniscule steady state levels of RhoP23H protein were found in photoreceptors of RhoP23H/+ mice (<5% the levels of wild-type RHO protein in rods) despite comparable levels of RhoP23H and wild-type RHO mRNA levels (Chiang et al., 2015). These findings reveal robust elimination of RhoP23H protein from rods by ERAD. Given that RHO protein is essential for photoreceptor function and survival, the disruption of RHO protein homeostasis found in RhoP23H/+ mice may underlie the molecular pathology of retinitis pigmentosa.

Important mechanistic questions to investigate about the pathogenesis of retinitis pigmentosa arising from RHO protein misfolding include: 1. What are the precise ERAD components that efficiently target RhoP23H for retrotranslocation from the ER and proteasomal degradation? 2. Does the loss of RHO protein in rods cause the retinal degeneration found in RhoP23H/+ mice? 3. Does the small amount of RhoP23H protein that escapes degradation also cause retinal degeneration found in RhoP23H/+ mice?

3. ER stress in Achromatopsia

Achromatopsia is an autosomal recessive vision disorder that affects 1 in 33,000 people in the United States. This blinding disease is characterized by cone photoreceptor dysfunction and degeneration. Patients with incomplete achromatopsia may have some color vision while those with complete achromatopsia can only see black, white, and shades of gray. Achromatic patients experience photophobia, nystagmus, and significantly impaired visual acuity. Symptoms typically manifest at birth or within the first few months of life. Mutations in cone phototransduction genes, GNAT2, PDE6C, PDE6H, CNGA3, and CNGB3 are found in ~80–90% of patients with achromatopsia (Chang et al., 2009; Kohl et al., 1998; Kohl et al., 2000; Kohl et al., 2012; Thiadens et al., 2009). Recently, a novel achromatopsia disease gene, ATF6, was identified in patients with achromatopsia but normal cone phototransduction genes (Ansar et al., 2015; Kohl et al., 2015; Xu et al., 2015).

ATF6 encodes an ER-resident transmembrane protein and regulates the UPR in parallel with IRE1 and PERK (Haze et al., 1999; Walter and Ron, 2011). In response to ER stress, the full-length ~90-kD ATF6 protein migrates from the ER to the Golgi apparatus where site 1 and site 2 proteases cleave the full-length protein to liberate the cytoplasmic portion of the ATF6 protein (Ye et al., 2000). The 50-kDa cytosolic ATF6 fragment contains a bZIP transcriptional activator. When freed by regulated intramembrane proteolysis during ER stress, the cytosolic ATF6 fragment translocates to the nucleus to activate its target genes that include many ER protein folding enzymes and chaperones, such as GRP78/BiP (Haze et al., 1999; Wu et al., 2007; Yamamoto et al., 2007). By this mechanism, ATF6 plays a key role during the UPR to maintain ER and cellular homeostasis.

ATF6 mutations in achromatopsia patients are distributed across the entire gene and include missense, nonsense, splice site, and frame shift mutations (Ansar et al., 2015; Kohl et al., 2015; Xu et al., 2015). Affected patients are homozygous or compound heterozygous for disease mutations. Fibroblasts collected from achromatopsia patients with ATF6 mutations revealed that ATF6 signaling was compromised in these cells. ATF6 mutations in the luminal domain, so-called Class 1 ATF6 mutations, impaired ER to Golgi trafficking of the full-length molecule during UPR. By contrast, ATF6 mutations in the cytosolic domain that truncated or damaged the bZIP/transcriptional activator, so-called Class 3 ATF6 mutations, prevented ATF6’s transcriptional induction of target genes during the UPR. Analysis of the retina in Atf6−/− mice also revealed photoreceptor dysfunction and photoreceptor cell death (Kohl et al., 2015). Interestingly, the retinal degeneration in mice affected both rods and cones and occurred only in aged mice. Put together, these findings identify ATF6 as a novel cause of achromatopsia, and they suggest that ER stress is an important pathogenetic mechanism underlying cone dysfunction.

Important mechanistic questions to address about the pathogenesis of achromatopsia arising from ATF6 loss include: 1. How does ATF6 regulate cone function and survival? 2. How does loss of ATF6 compromise photoreceptor function? All other achromatopsia disease genes regulate cone phototransduction. By contrast, ATF6 regulates ER homeostasis as part of the UPR. It is important to determine whether ATF6 might play a novel role in regulating phototransduction in cones.

4. Conclusions

In summary, cones and rods are essential for vision, and many blinding disease arise when photoreceptors are damaged. The high metabolic demands of photoreceptors may cause them to be highly sensitive to ER stress. We show that ER stress and UPR signaling are vital mechanisms underlying two specific photoreceptor diseases. In retinitis pigmentosa arising from RHO mutations, misfolded RHO protein produces ER stress in rod photoreceptors that triggers the IRE1 branch of the UPR. In achromatopsia, ATF6 mutations are a novel cause of cone photoreceptor dysfunction, and these mutations lead to loss of ATF6 function and potentially dysregulation of ER stress levels and UPR in cone photoreceptors. Deciphering cell-type specific functions of UPR in cones and rods are essential to understand the pathogenesis of these two photoreceptor diseases. Furthermore, molecular approaches to improve protein folding, reduce ER stress, or target specific UPR chaperones and genes in photoreceptors may provide novel therapeutic alternatives for retinal degeneration diseases. Insights gained from these studies may also benefit other diseases of the eye including glaucoma and age-related macular degeneration where ER stress and UPR signaling have also been described.

Highlights.

  • ER stress and UPR are pathomechanisms of rod and cone photoreceptor diseases.

  • Rhodopsin misfolding is a cause of rod photoreceptor disease, retinitis pigmentosa.

  • Rod photoreceptors degrade misfolded rhodopsin through ERAD.

  • ATF6 mutations are a novel cause of cone photoreceptor disease, achromatopsia.

  • Achromatopsia mutations target sequential steps of ATF6 activation.

Footnotes

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