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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 F 0 -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.

human molecular genetics

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium of  Cln3 Δex1-6   mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)