Failure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice

Author(s)
Von Eisenhart-Rothe, Philipp
Grubman, Alexandra
Greferath, Ursula
Fothergill, Linda J
Jobling, Andrew I
Phipps, Joanna A
White, Anthony R
Fletcher, Erica L
Vessey, Kirstan A
Publication Date
2018-10
Abstract
<p><b>PURPOSE.</b> Vision loss caused by photoreceptor death represents one of the first symptoms in neuronal ceroid lipofuscinosis, a condition characterized by accumulation of intracellular waste. <i>Cln6<sup>nclf</sup></i> mice have a naturally occurring mutation in ceroid–lipofuscinosis neuronal (CLN) protein 6 and are a model of this disorder. In order to identify the effect intracellular waste (lipofuscin) accumulation plays in driving retinal degeneration, the time course of degeneration was carefully characterized functionally using the electroretinogram and structurally using histology.</p> <p><b>METHODS.</b> <i>Cln6<sup>nclf</sup></i> and C57BL/6J, wild-type, mice were studied at postnatal day 18 (P18), P30, P60, P120, and P240, and retinal degeneration was correlated with changes in the retinal pigment epithelial (RPE) and neuronal autophagy–lysosomal pathways using super-resolution microscopy.</p> <p><b>RESULTS.</b> In <i>Cln6<sup>nclf</sup></i> mice there was significant loss of rod photoreceptor function at P18, prior to photoreceptor nuclei loss at P60. In contrast, cone pathway function was not affected until P240. The loss of rod photoreceptor function correlated with significant disruption of the autophagy–lysosomal degradation pathways within photoreceptors, but not in the RPE or other retinal neurons. Additionally, there was cytosolic accumulation of P62 and undigested mitochondrial-derived, ATP synthase subunit C in the photoreceptor layers of <i>Cln6<sup>nclf</sup></i> mice at P30.</p> <p><b>CONCLUSIONS.</b> These results suggest that rod photoreceptors have an increased sensitivity to disturbances in the autophagy–lysosomal pathway and the subsequent failure of mitochondrial turnover, relative to other retinal cells. It is likely that primary failure of the rod photoreceptors rather than the RPE or other retinal neurons underlies the early visual dysfunction that occurs in the <i>Cln6<sup>nclf</sup></i> mouse model.</p>
Citation
Investigative Ophthalmology & Visual Science, 59(12), p. 5082-5097
ISSN
1552-5783
0146-0404
Link
Publisher
Association for Research in Vision and Ophthalmology
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Title
Failure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice
Type of document
Journal Article
Entity Type
Publication

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