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

Title: Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of Cln3Δex1-6 mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)
Authors: Wavre-Shapton, ST
Calvi, AA
Turmaine, M
Seabra, MC
Cutler, DF
Futter, CE
Mitchison, HM
Item Type: Journal Article
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 Cln3Δex1-6 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 Cln3Δex1-6 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 Cln3Δex1-6-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 Cln3Δex1-6 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.
Issue Date: 8-Oct-2015
Date of Acceptance: 22-Sep-2015
URI: http://hdl.handle.net/10044/1/41155
DOI: http://dx.doi.org/10.1093/hmg/ddv406
ISSN: 1460-2083
Publisher: Oxford University Press
Start Page: 7060
End Page: 7074
Journal / Book Title: Human Molecular Genetics
Volume: 24
Issue: 24
Copyright Statement: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Fight For Sight
Funder's Grant Number: 093445/Z/10/Z
1936
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
KNOCKOUT MOUSE MODEL
MACULAR DEGENERATION
OUTER SEGMENTS
CLN3 PROTEIN
GENE CLN3
PHAGOCYTOSIS
TRANSPORT
CELLS
RECEPTOR
MITOCHONDRIAL
Aging
Animals
Autophagy
Brain
Disease Models, Animal
Lysosomes
Membrane Fusion
Membrane Glycoproteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Microspheres
Mitochondrial Proton-Translocating ATPases
Molecular Chaperones
Neuronal Ceroid-Lipofuscinoses
Neurons
Phagosomes
Retinal Pigment Epithelium
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:National Heart and Lung Institute