ArticleCell death & disease2019
Shifting the balance of autophagy and proteasome activation reduces proteotoxic cell death: a novel therapeutic approach for restoring photoreceptor homeostasis.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 66 citations in OpenAlex.
- Enhanced Endocytosis and Mitochondrial Stress Underlie Severe Retinitis Pigmentosa With RHO P347L Mutant.Investigative ophthalmology & visual science · 2026Article
- Enhancing Experience-Dependent Plasticity Accelerates Vision Loss in a Murine Model of Retinitis Pigmentosa.Investigative ophthalmology & visual science · 2026Article
- Targeting endoplasmic reticulum stress in diabetic retinopathy: mechanistic insights and emerging therapies.Biological research · 2026Review
- Endoplasmic reticulum: the target of chlamydial manipulation.Archives of microbiology · 2025Review
- Neuroprotection of photoreceptors by combined inhibition of both Fas and autophagy pathways in P23H mice.Cell death & disease · 2025Article
- Article
- Impairment of proteasome-associated deubiquitinating enzyme Uchl5/UBH-4 affects autophagy.Biology open · 2025Article
- Mechanisms of Rhodopsin-Related Inherited Retinal Degeneration and Pharmacological Treatment Strategies.Cells · 2025Review
- Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor.Cell death & disease · 2024Article
- Aggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa.Nature communications · 2024Article
- Molecular mechanisms underlying inherited photoreceptor degeneration as targets for therapeutic intervention.Frontiers in cellular neuroscience · 2024Review
- The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.Progress in retinal and eye research · 2024Review
- Therapeutic potential of archaeal unfoldase PANet and the gateless T20S proteasome in P23H rhodopsin retinitis pigmentosa mice.PloS one · 2024Article
- Cell-cell interaction in the pathogenesis of inherited retinal diseases.Frontiers in cell and developmental biology · 2024Review
- Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Endogenous and Exogenous Regulation of Redox Homeostasis in Retinal Pigment Epithelium Cells: An Updated Antioxidant Perspective.International journal of molecular sciences · 2023Review
- Pathomechanisms of Inherited Retinal Degeneration and Perspectives for Neuroprotection.Cold Spring Harbor perspectives in medicine · 2023Review
- PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.The Journal of cell biology · 2023Article
- Sigma 1 receptor activation improves retinal structure and function in the RhoExperimental eye research · 2023Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The P23H variant of rhodopsin results in misfolding of the protein, and is a common cause of the blinding disease autosomal dominant retinitis pigmentosa (adRP). We have recently demonstrated that degeneration of photoreceptor cells in retinas of P23H mice is due to the endoplasmic reticulum stress (ERS)-induced activation of autophagy that leads to a secondary proteasome insufficiency and activation of cell death pathways. We propose that this increased level of autophagy flux relative to proteasome activity, which we term the A:P ratio, represents a marker of altered photoreceptor cell homeostasis, and that therapies aimed at normalizing this ratio will result in increased photoreceptor cell survival. To test this postulate, we treated P23H mice with a chemical chaperone (4-phenylbutyric acid) to improve rhodopsin folding, or with a selective phosphodiesterase-4 inhibitor (rolipram) to increase proteasome activity. P23H mice treated with either of these agents exhibited reduced ERS, decreased autophagy flux, increased proteasome activity, and decreased activation of cell death pathways. In addition, rates of retinal degeneration were decreased, and photoreceptor morphology and visual function were preserved. These findings support the conclusion that normalizing the A:P ratio, either by reducing the ERS-induced activation of autophagy, or by increasing proteasome activity, improves photoreceptor survival, and suggest a potential new therapeutic strategy for the treatment of adRP caused by protein folding defects.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.