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Hum Mol Genet. 2015 Dec 15;24(24):7060-74. doi: 10.1093/hmg/ddv406. Epub 2015 Oct 8.

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease).

Author information

1
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK, Molecular Medicine, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
2
Nuclear Dynamics and Architecture, Institute of Medical Biology, Singapore 138648, Singapore.
3
Faculty of Life Sciences, Division of Biosciences and.
4
Molecular Medicine, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.
5
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK and MRC Cell Biology Unit, MRC Laboratory for Molecular Cell Biology, London, UK.
6
UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK, h.mitchison@ucl.ac.uk c.futter@ucl.ac.uk.
7
Genetics and Genomic Medicine Programme and Birth Defects Research Centre, Institute of Child Health, University College London, London WC1N 1EH, UK, h.mitchison@ucl.ac.uk c.futter@ucl.ac.uk.

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.

PMID:
26450516
PMCID:
PMC4654058
DOI:
10.1093/hmg/ddv406
[Indexed for MEDLINE]
Free PMC Article

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