Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice-An Animal Model of CLN10 Disease.

Abstract

Vision loss is among the characteristic symptoms of neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative lysosomal storage disorder. Here, we performed an in-depth analysis of retinal degeneration at the molecular and cellular levels in mice lacking the lysosomal aspartyl protease cathepsin D, an animal model of congenital CLN10 disease. We observed an early-onset accumulation of storage material as indicated by elevated levels of saposin D and subunit C of the mitochondrial ATP synthase. The accumulation of storage material was accompanied by reactive astrogliosis and microgliosis, elevated expression of the autophagy marker sequestosome 1/p62 and a dysregulated expression of several lysosomal proteins. The number of cone photoreceptor cells was reduced as early as at postnatal day 5. At the end stage of the disease, the outer nuclear layer was almost atrophied, and all cones were lost. A significant loss of rod and cone bipolar cells, amacrine cells and ganglion cells was found at advanced stages of the disease. Results demonstrate that cathepsin D deficiency results in an early-onset and rapidly progressing retinal dystrophy that involves all retinal cell types. Data of the present study will serve as a reference for studies aimed at developing treatments for retinal degeneration in CLN10 disease.

• Authors: Mahmoud Bassal, Junling Liu, Wanda Jankowiak, Paul Saftig, Udo Bartsch
• Journal: Cells (Cells) Vol. 10 Issue 3 (03 21 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 33800998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Subunits
• Sequestosome-1 Protein
• Sqstm1 protein, mouse
• Cathepsin D
• Mitochondrial Proton-Translocating ATPases

Topics

• Animals
• Autophagy
• Cathepsin D (deficiency, metabolism)
• Disease Models, Animal
• Gliosis (pathology)
• Lysosomes (metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Proton-Translocating ATPases (metabolism)
• Neuronal Ceroid-Lipofuscinoses (complications, pathology)
• Photoreceptor Cells (metabolism, pathology)
• Protein Subunits (metabolism)
• Retina (pathology)
• Retinal Degeneration (complications, pathology)
• Sequestosome-1 Protein (metabolism)
• Mice