ER stress in retinal degeneration: a target for rational therapy?

Mutations that cause rhodopsin misfolding and retention within the endoplasmic reticulum (ER) are a prominent cause of retinitis pigmentosa. Here, we discuss the hypothesis that the failure of photoreceptor neurons to adapt to the stress caused by rhodopsin accumulation in the ER leads to a global collapse of homeostasis and to retinal degeneration. We review the molecular mechanisms underlying the activity of local ER conformational sensors and stress-relaying modules and consider how ER-derived stress signals are amplified and implemented to impact on downstream processes, including rhodopsin clearance and cell fate control. The emerging view is that alterations to the systems responsible for the detection, transduction and implementation of ER stress might be used therapeutically to treat retinitis pigmentosa. Mutations that cause rhodopsin misfolding and retention within the endoplasmic reticulum (ER) are a prominent cause of retinitis pigmentosa. Here, we discuss the hypothesis that the failure of photoreceptor neurons to adapt to the stress caused by rhodopsin accumulation in the ER leads to a global collapse of homeostasis and to retinal degeneration. We review the molecular mechanisms underlying the activity of local ER conformational sensors and stress-relaying modules and consider how ER-derived stress signals are amplified and implemented to impact on downstream processes, including rhodopsin clearance and cell fate control. The emerging view is that alterations to the systems responsible for the detection, transduction and implementation of ER stress might be used therapeutically to treat retinitis pigmentosa. an ATP analog that binds selectively to the kinase domain of mutant versions of IRE1, which have been engineered to exhibit an enlarged ATP-binding site. As a result, 1NM-PP1 application activates IRE1 kinase and, subsequently, endoribonuclease activities. a vitamin A-based chromophore that changes conformation and is isomerized to all-trans retinal upon light exposure when bound to opsin. a virus that infects dividing and nondividing cells in humans and other primates. AAV does not induce strong immunological responses and it might incorporate its genome into that of the host cell at specific sites. AAV is extensively used for gene therapy. proteins that contain a BCL2 homology (BH) 3 domain. BH3 only proteins disable mitochondrial protecting proteins (BCL2, BCL-XL, MCL1) and trigger the oligomerization of the multidomain proteins Bax and Bak that open the membrane transition permeability pore, thereby leading to the release of the intermembrane mitochondrial proteins and apoptosis. a low molecular weight compound that nonselectively stabilizes misfolded proteins (including nontarget proteins) and facilitates their folding. a light-sensitive photoreceptor neuron (PN) that functions in bright light and mediates both high acuity and color vision in humans. the layer of the vertebrate retina containing synapses between dendrites of horizontal cells from the inner nuclear layer and photoreceptor inner segments from the outer nuclear layer. the layer of the vertebrate retina containing several strata of nuclear bodies of the rod and cone photoreceptor cells. a low molecular weight compound that promotes the correct folding of misfolded proteins in a substrate-specific manner. this uses the transformation of protein structures into residue interaction graphs, where amino acid residues are graph nodes and their interactions with each other are the graph edges. cell layer situated behind the retina that is involved in the phagocytosis of the photoreceptor outer segment. the extraction of misfolded proteins from the ER and their transport to the cytosol; retrotranslocated proteins are typically delivered to the proteasome for degradation. a light-sensitive photoreceptor neuron (PN) that is highly sensitive (up to a single photon level), and mediates peripheral and dim light (scotopic) vision. the middle, 'housekeeping' region of the rod photoreceptor containing mitochondria and the apparatus for protein synthesis, including the ER. the light-sensitive outer portion of a rod photoreceptor cell containing a stack of disk membranes laden with tightly packed visual pigments. used to accelerate conformational changes in biomolecular systems through the application of external forces. the administration of fluid/medication between the photoreceptors and retinal pigment epithelium. a heterotrimeric G protein containing α, β and γ subunits. Transducin is activated by a conformational change in rhodopsin owing to the absorption of a photon by 11-cis-retinal, leading to the activation of the vertebrate phototransduction cascade.