ArticleHuman molecular genetics2015
Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease).
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial.Retina (Philadelphia, Pa.) · 2019Trial
- Reversible synaptic deficits in early-stage batten disease.Journal of translational medicine · 2026Article
- Acid sphingomyelinase inhibition restores RPE homeostasis and photoreceptor function in preclinical Stargardt macular degeneration models.bioRxiv : the preprint server for biology · 2026Article
- Elevated tripeptidyl-peptidase 1 corrects multiple disease phenotypes in a mouse model of juvenile neuronal ceroid lipofuscinosis.Molecular therapy. Methods & clinical development · 2025Article
- Genetic and Cellular Basis of Impaired Phagocytosis and Photoreceptor Degeneration in CLN3 Disease.Investigative ophthalmology & visual science · 2024Article
- Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.Communications biology · 2024Article
- Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model.Neurobiology of disease · 2024Article
- A recessiveJournal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc · 2024Article
- Age-Related RPE changes in Wildtype C57BL/6J Mice between 2 and 32 Months.bioRxiv : the preprint server for biology · 2024Article
- Long-term progression of retinal degeneration in a preclinical model of CLN7 Batten disease as a baseline for testing clinical therapeutics.EBioMedicine · 2022Article
- Experimental Therapeutic Approaches for the Treatment of Retinal Pathology in Neuronal Ceroid Lipofuscinoses.Frontiers in neurology · 2022Review
- Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.Molecules (Basel, Switzerland) · 2021Review
- CLN3, at the crossroads of endocytic trafficking.Neuroscience letters · 2021Article
- Visual system pathology in a canine model of CLN5 neuronal ceroid lipofuscinosis.Experimental eye research · 2021Article
- Article
- A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor-RPE interface.Communications biology · 2021Article
- Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium.Biochimica et biophysica acta. Molecular basis of disease · 2020Article
- Cellular models of Batten disease.Biochimica et biophysica acta. Molecular basis of disease · 2020Review
- Impairment of Lysosome Function and Autophagy in Rare Neurodegenerative Diseases.Journal of molecular biology · 2020Review
- The cell biology of the retinal pigment epithelium.Progress in retinal and eye research · 2020Review
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations, followed by inevitable progression to blindness. We investigated retinal degeneration in Cln3(Δex1-6) null mice, revealing classic 'fingerprint' lysosomal storage in the retinal pigment epithelium (RPE), replicating the human disease. The lysosomes contain mitochondrial F0-ATP synthase subunit c along with undigested membranes, indicating a reduced degradative capacity. Mature autophagosomes and basal phagolysosomes, the terminal degradative compartments of autophagy and phagocytosis, are also increased in Cln3(Δex1) (-6) RPE, reflecting disruption to these key pathways that underpin the daily phagocytic turnover of photoreceptor outer segments (POS) required for maintenance of vision. The accumulated autophagosomes have post-lysosome fusion morphology, with undigested internal contents visible, while accumulated phagosomes are frequently docked to cathepsin D-positive lysosomes, without mixing of phagosomal and lysosomal contents. This suggests lysosome-processing defects affect both autophagy and phagocytosis, supported by evidence that phagosomes induced in Cln3(Δex1) (-) (6)-derived mouse embryonic fibroblasts have visibly disorganized membranes, unprocessed internal vesicles and membrane contents, in addition to reduced LAMP1 membrane recruitment. We propose that defective lysosomes in Cln3(Δex1) (-) (6) RPE have a reduced degradative capacity that impairs the final steps of the intimately connected autophagic and phagocytic pathways that are responsible for degradation of POS. A build-up of degradative organellar by-products and decreased recycling of cellular materials is likely to disrupt processes vital to maintenance of vision by the RPE.
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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.