Failure of Autophagy-Lysosomal Pathways in Rod Photoreceptors Causes the Early Retinal Degeneration Phenotype Observed in Cln6nclf Mice
| Autor: | Alexandra Grubman, Anthony R. White, Kirstan A. Vessey, Joanna A. Phipps, Andrew I Jobling, Philipp von Eisenhart-Rothe, Ursula Greferath, Linda J Fothergill, Erica L. Fletcher |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Retinal degeneration genetic structures Blotting Western Cell Count Retinal Pigment Epithelium Retina Lipofuscin 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Neuronal Ceroid-Lipofuscinoses Retinal Rod Photoreceptor Cells medicine Autophagy Electroretinography Animals Retinal pigment epithelium Microscopy Confocal medicine.diagnostic_test Retinal Degeneration Membrane Proteins Retinal General Medicine medicine.disease eye diseases Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Phenotype chemistry Neuronal ceroid lipofuscinosis sense organs Lysosomes 030217 neurology & neurosurgery Photic Stimulation Signal Transduction |
| Zdroj: | Investigative ophthalmologyvisual science. 59(12) |
| ISSN: | 1552-5783 |
| Popis: | Purpose Vision loss caused by photoreceptor death represents one of the first symptoms in neuronal ceroid lipofuscinosis, a condition characterized by accumulation of intracellular waste. Cln6nclf 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. Methods Cln6nclf 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. Results In Cln6nclf 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 Cln6nclf mice at P30. Conclusions 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 Cln6nclf mouse model. |
| Databáze: | OpenAIRE |
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