Rat models carrying a transgene expressing the mouse rhodopsin gene ( Rho) with a C-A substitution at codon 23 (P23H amino acid conversion) were first described in Steinberg et al. However, the precise mechanisms that lead to photoreceptor loss are not well understood. Although not entirely clear, it is likely that the resultant recruitment of ER-resident chaperones and activation of ubiquitin/proteasome system ( Chapple et al., 2001) becomes overwhelmed resulting in ER stress and activation of the unfolded protein response (UPR), which in turn leads to photoreceptor death ( Chiang et al., 2012, 2015, 2016 Athanasiou et al., 2017). P23H-RHO is thought to cause improper folding at the N-terminal, the binding site of 11- cis-retinal, resulting in the formation of dysfunctional, oligomeric aggregates within the endoplasmic reticulum (ER) and Golgi ( Chapple et al., 2001). More than 150 different mutations have been identified in RHO, but the most frequent is a single-base C-to-A transversion, resulting in substitution of proline for histidine in codon 23 (P23H), causing autosomal dominant RP ( Dryja et al., 1990 Athanasiou et al., 2018). While approximately 96 different mutated genes have been identified in patients with RP (RetNet November 2019) 1, mutations in rhodopsin ( RHO) are the most common causes of RP, accounting for approximately 15% of all inherited human retinal degenerations ( Chapple et al., 2001) and 30–40% of patients with the autosomal dominant form of the disease ( Ferrari et al., 2011). Retinitis pigmentosa (RP) is the most common form of inherited retinopathy, characterized by progressive loss of photoreceptors (rods and cones), which leads to severe visual impairment ( Guadagni et al., 2015 Bravo-Gil et al., 2017). Photoreceptor death causes approximately 50% of all cases of irreversible vision loss in the western world ( Taylor et al., 2005). These findings highlight the complexity of mechanisms involved in photoreceptor death in the Pro23His rat model of degeneration and suggest therapies that target necroptosis should be considered for their potential to reduce photoreceptor death. By contrast, reverse-phase protein array data combined with RIPK3 and phospho-MLKL immunofluorescence indicated widespread necroptosis as the predominant mechanism of photoreceptor death. However, analysis of mitochondrial permeability changes (ΔΨm) using JC-1 dye, combined with immunofluorescence markers for caspase-dependent (cleaved caspase-3) and caspase-independent (AIF) cell death pathways, indicated mitochondrial-mediated cell death was not a major contributor to photoreceptor death. Focused gene expression arrays indicated activation of, apoptosis, autophagy and necroptosis in whole retina from P14-18. TUNEL analysis showed extensive cell death at P18, with continued labeling detected until P30. The cone-mediated b-wave was also decreased from P30. Electroretinogram analyses revealed significantly decreased rod photoreceptor (a-wave), bipolar cell (b-wave) and amacrine cell responses (oscillatory potentials) from P30 onward. We first used electroretinogram recording and optical coherence tomography to confirm the time course of functional and structural loss. However, the mechanism(s) by which photoreceptor death occurs are not well understood and were the principal aim of this study. Pro23His (P23H) transgenic albino rat strains are widely used models for the most common rhodopsin gene mutation associated with the autosomal dominant form of retinitis pigmentosa. Such a link appears to be the manifestation of intrinsic chromophore features associated with the existence of a conical intersection between its ground and excited states.Photoreceptor death contributes to 50% of irreversible vision loss in the western world. The transition state mediating thermal activation has the same electronic structure as the photoreceptor excited state, thus creating a direct link between λ max and k. Here we show that a quantum chemical model of the bovine rod pigment provides a molecular-level understanding of the Barlow correlation. Although the mechanism of such a process is under debate, the observation of a relationship between the maximum absorption wavelength (λ max) and the thermal activation kinetic constant (k) of different visual pigments (the Barlow correlation) indicates that the thermal and photochemical activations are related. Their origin is attributed to a thermal, rather than photochemical, activation of the transduction cascade. Spontaneous electrical signals in the retina's photoreceptors impose a limit on visual sensitivity.
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