Jul 2026· The FASEB Journal· Vol 40 15, pp.
e72130
· 0 citations· 97 references
Medicine
TL;DR
The hypothesis that there is a biochemical link, most likely the UPR, between rhodopsin folding/misfolding status and metabolic homeostasis is supported and targeted metabolic modulation may offer a complementary therapeutic avenue for treating RP.
Abstract
Retinitis pigmentosa (RP) is a hereditary retinal degeneration disorder often caused by mutations in the rhodopsin gene, leading to photoreceptor death and vision loss. While structural misfolding of rhodopsin is a known contributor to disease pathology, the mechanisms of its cellular and in particular metabolic consequences are poorly understood. To study the direct effects of rhodopsin misfolding and structural rescue on cellular metabolism, we used the P23A mutant and its N2C/D282C stabilized counterpart as a structural tool to assess how differences in folding stability relate to measurable changes at the metabolite level. The engineered cysteine pair allows the formation of a disulfide bond restoring structural integrity and reinforcing the stable seven-transmembrane bundle. We used untargeted Gas Chromatography-Mass Spectrometry (GC-MS) metabolomics analysis conducted in inducible rhodopsin-expressing cell lines, providing a broad and general profiling of metabolic pathway alterations in response to the expression of RP mutants and their structurally rescued counterparts. Principal component analysis, hierarchical clustering, and K-means clustering revealed distinct metabolic signatures associated with each rhodopsin-expressing cell line, demonstrating a highly significant effect of genotype on global metabolite composition (F = 71.679; R2 = 0.93724; p = 0.001). Pairwise comparisons and background-subtracted analyses identified consistent alterations in arginine and proline metabolism, glutathione metabolism, and the TCA cycle, nucleotide, amino acid metabolism, redox regulation, and mitochondrial function in cells expressing misfolded P23A. Pathway enrichment highlighted key metabolites in the respective pathways as candidate biomarkers for the rhodopsin P23A mutation. As this study employs a non-retinal cell system, the observed metabolic changes reflect conserved responses to rhodopsin misfolding and proteostatic stress in the ER rather than a direct model of rod cell degeneration. Our findings support the hypothesis that there is a biochemical link, most likely the UPR, between rhodopsin folding/misfolding status and metabolic homeostasis and suggest that targeted metabolic modulation may offer a complementary therapeutic avenue for treating RP.
A high-resolution map of RHO missense variant trafficking using deep mutational scanning approaches, including a surface abundance immunoassay and a complementary membrane proximity assay, provides a valuable resource for pathogenicity assessment, genotype-phenotype correlations, and the development of targeted therapeutic strategies for RHO-adRP.
K. Manian, Connor H. Ludwig, Yan Zhao et al.· Science Advances· 0 citations
A new genetic model for studies of splicing-factor associated RP is established that recapitulates aspects of the human disease and suggests that antioxidants might serve as a treatment for individuals with SNRNP200-associated RP.
Sara K. Mayer, Quinton H Christensen, Hailey McCoy-Munger et al.· Human Molecular Genetics· 0 citations
It is suggested that ABCA4 deficiency in photoreceptor discs may trigger early stress-associated transcriptomic responses in retinal glial cells prior to overt photoreceptor degeneration, potentially contributing to Stargardt disease pathogenesis.
Rossella Valenzano, A. McDonald, C. Gallego et al.· Stem Cells· 0 citations
Summary Inherited retinal diseases (IRDs) encompass a broad spectrum of genetic conditions leading to visual impairment. In this study, we identify KATNA1, encoding the catalytic p60 subunit of the microtubule-severing enzyme katanin, as a previously unrecognized cause of autosomal dominant macular dystrophy (adMD), a form of IRD. Specifically, we could ascertain the presence of 10 heterozygous missense changes affecting six conserved amino acids in 21 individuals from 16 unrelated families from various parts of the world, all presenting with non-syndromic MD of variable severity. Structure-guided analyses indicated that the identified variants potentially disrupt katanin’s assembly into hexamers or its ability to bind or hydrolyze ATP, thus compromising its microtubule-severing function. Characterization of patient-derived fibroblasts revealed accumulation of acetylated microtubules both in the cytoplasm and within the primary cilium, together with an altered subcellular distribution of KATNA1. Immunostaining of human retinal tissue showed that KATNA1 specifically localizes to photoreceptors, with distinct distribution patterns between rod and cone photoreceptors. Immunogold transmission electron microscopy confirmed this finding, revealing KATNA1 distribution along the rod axoneme and predominantly within the cone connecting cilium. Together, these results establish KATNA1 as a novel gene associated with adMD, possibly accounting for ~4% of all unresolved MD cases, and associate defective microtubule severing and cytoskeletal dysregulation with macular degeneration.
Carlo Rivolta, Karolina Kaminska, Abigail R. Moye et al.· Research Square· 0 citations
ABSTRACT
Inherited retinal degenerative diseases, such as retinitis pigmentosa, cause progressive photoreceptor loss and irreversible vision decline, yet effective treatments remain unavailable. Our previous studies demonstrated that Lycium barbarum glycopeptide delays photoreceptor degeneration in a chemically induced retinitis pigmentosa model, primarily through antiinflammatory mechanisms. In this study, we extended these findings to an inherited retinitis pigmentosa model to further elucidate the neuroprotective actions of Lycium barbarum glycopeptide. Lycium barbarum glycopeptide was orally administered daily to rd10 mice beginning at postnatal day 8, prior to photoreceptor degeneration, and retinal function and morphology were evaluated at postnatal day 25, the peak of rod apoptosis. Behavioral assays, electroretinography, immunofluorescence staining, proteomic profiling, and western blotting were performed to assess the therapeutic effects and molecular mechanisms of Lycium barbarum glycopeptide. Lycium barbarum glycopeptide treatment significantly improved visual performance in rd10 mice, as shown by enhanced optomotor responses and black.white transition behavior. Electroretinography analysis revealed increased scotopic a-wave amplitudes, indicating improved photoreceptor function. Histological evaluation showed preservation of outer nuclear layer thickness and maintenance of rod and cone opsin expression. Lycium barbarum glycopeptide also reduced microglial and Muller glial activation in a region-dependent manner. Proteomic and biochemical analyses revealed that Lycium barbarum glycopeptide upregulated key phototransduction proteins while concurrently downregulating pro-inflammatory mediators such as interleukin-6, nuclear factor kappa B, cyclooxygenase-2, and tumor necrosis factor-α. Collectively, these results demonstrate that Lycium barbarum glycopeptide protects against inherited photoreceptor degeneration by improving retinal function and structure, alleviating neuroinflammation, and supporting phototransduction recovery. This work extends our previous findings and highlights Lycium barbarum glycopeptide as a promising therapeutic candidate for inherited retinal degenerative diseases.
Central areolar choroidal dystrophy (CACD) is a progressive macular dystrophy without treatment. Although PRPH2 mutations are the most common cause of disease, the mechanisms driving their phenotypic variability remain poorly understood. Here, a comprehensive characterization of the pathophysiological consequences of p.Arg195Leu mutation in PRPH2 was carried out in a mouse model (Prph2
KI/WT
). For evaluating the retinal degeneration, this study combines the analysis of electroretinographic responses together with a complete study of bulk RNA-seq transcriptomics and the key cellular and molecular pathways using confocal imaging, flow-cytometry and western blotting. Results from this work demonstrate that ageing and sex influence retinal degeneration. In young mutant mice, retinal functional impairment and structural disorganization of photoreceptor outer segments were accompanied by a reduced expression of Prph2 and Rom1 genes, together with the activation of the immune system and complement pathways. Middle-age stages represent a critical transition point where the increase of cell death and epithelial barrier dysfunction mark the beginning of retinal degeneration. These pathological events become evident at 9 months of age, where visual pathways-related genes were deregulated. Functional, cellular and molecular alterations observed in the mutant mice do not affect males and females equally. From the earliest stages of the disease, females exhibited greater and sustained inflammatory activation, mainly promoted by complement system upregulation and increased CD11b immunoreactivity, and potentially mediated by IL-6/STAT3/ERK signaling. Moreover, females had greater functional decline and photoreceptor loss. Together, these results could explain the high inter- and intrafamilial variability observed in CACD patients carrying the same mutation. Our findings identify inflammatory biomarkers accompanied by visual function loss, prior to evident retinal degeneration, and demonstrate that age and sex critically shape disease onset and severity. These insights underscore the necessity of incorporating sex-specific biology and early anti-inflammatory treatment into the development of targeted therapies for PRPH2-related dystrophies.
Enola Missonnier, Lorena Vidal-Gil, Carla Sánchez-Castillo et al.· Cell Death Discovery· 0 citations