We previously found that valproic acid (VPA) and other histone deacetylase inhibitors (HDACis) ameliorate retinal degeneration (RD) caused by P23H rhodopsin in Xenopus laevis larvae and hypothesized that this may be due to enhancement of autophagy. Here we use X. laevis expressing an autophagy marker to assess effects of HDACis on autophagy. We also assess the effects of non-HDACi activators and inducers of autophagy on RD caused by P23H rhodopsin.
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Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa.
PLoS Biol
January 2025
Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America.
Pathogenic mutations that cause rhodopsin misfolding lead to a spectrum of currently untreatable blinding diseases collectively termed retinitis pigmentosa. Small molecules to correct rhodopsin misfolding are therefore urgently needed. In this study, we utilized virtual screening to search for drug-like molecules that bind to the orthosteric site of rod opsin and improve its folding and trafficking.
View Article and Find Full Text PDFOptimization of HITI-Mediated Gene Insertion for Rhodopsin and Peripherin-2 in Mouse Rod Photoreceptors: Targeting Dominant Retinitis Pigmentosa.
Invest Ophthalmol Vis Sci
November 2024
Laboratory for Retinal Regeneration, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
Purpose: Among the genome-editing methods for repairing disease-causing mutations resulting in autosomal dominant retinitis pigmentosa, homology-independent targeted integration (HITI)-mediated gene insertion of the normal form of the causative gene is useful because it allows the development of mutation-agnostic therapeutic products. In this study, we aimed for the rapid optimization and validation of HITI-treatment gene constructs of this approach in developing HITI-treatment constructs for various causative target genes in mouse models of retinal degeneration.
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bioRxiv
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Department of Ophthalmology & Visual Sciences and Department of Biochemistry & Molecular Medicine, West Virginia University, Morgantown, WV 26506, United States.
Rod photoreceptor neurons in the retina detect scotopic light through the visual pigment rhodopsin (Rho) in their outer segments (OS). Efficient Rho trafficking to the OS through the inner rod compartments is critical for long-term rod health. Given the importance of protein trafficking to the OS, less is known about the trafficking of rod synaptic proteins.
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Mol Cell Proteomics
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School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. Electronic address:
Article Synopsis
- Inherited retinal degenerations (IRDs) are a leading cause of blindness in young people, often starting with night vision loss and visual field decline, primarily seen in retinitis pigmentosa (RP).
- The study used different mouse models representing various types of RP and Leber’s congenital amaurosis to analyze retinal proteins, employing consistent methods across institutions for reliable results.
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Therapeutic potential of archaeal unfoldase PANet and the gateless T20S proteasome in P23H rhodopsin retinitis pigmentosa mice.
PLoS One
October 2024
Department of Ophthalmology, West Virginia University, Morgantown, West Virginia, United States of America.
Neurodegenerative diseases are characterized by the presence of misfolded and aggregated proteins which are thought to contribute to the development of the disease. In one form of inherited blinding disease, retinitis pigmentosa, a P23H mutation in the light-sensing receptor, rhodopsin causes rhodopsin misfolding resulting in complete vision loss. We investigated whether a xenogeneic protein-unfolding ATPase (unfoldase) from thermophilic Archaea, termed PANet, could counteract the proteotoxicity of P23H rhodopsin.
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