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.

Retinal Degeneration and Microglial Dynamics in Mature Progranulin-Deficient Mice

“…Therefore, PGRN in the retina might also play important roles in the maintenance of lysosomal function and homeostatic balance in these cells. In other mouse models of CNLs, similar phenotypes, including dysregulation of lysosomes and excessive gliosis in the inner retina, have been reported [ 8 , 11 , 12 ]. In contrast, the expression of lysosomal proteins in the RPE-choroid was not affected by PGRN deficiency, while the highest expression of PGRN was observed in the RPE-choroid complex in the ocular sections of Grn +/+ mice ( Figure 4 ).…”

“…The causative genes of the several distinct NCL subtypes are called CLNs (CLN1-CLN8 and CLN10-CLN14). Transgenic or naturally occurring mouse models that show characteristic retinal phenotypes are available for most CLNs [ 8 , 9 , 10 , 11 , 12 ]. In addition, various mouse models of PGRN deficiency have been generated for CLN11, which is caused by homozygous Grn gene mutations, and retinal degeneration and the deposition of autofluorescent aggregates have been characterized in these mice [ 6 , 13 , 14 ].…”

Release of Iron-Loaded Ferritin in Sodium Iodate-Induced Model of Age Related Macular Degeneration: An In-Vitro and In-Vivo Study

“…It is likely that NaIO 3 suppresses the transcription or increases the degradation of its mRNA, resulting in a significant reduction in its mRNA in NaIO 3 -treated cells. Consistent with these observations, a homozygous knockout mouse model of cat-D develops drusen deposits and retinal dysfunction by 12 months of age, and mice with deletions in cat-D that decrease the level of mature enzyme develop rapid and progressive loss of multiple retinal cell types, underscoring the significance of this enzyme in AMD pathogenesis [ 49 ]. However, neither mouse model developed choroidal neovascularization, a feature of wet AMD, indicating that impaired function of cat-D leads to dry AMD.…”

Formation of Lipofuscin-Like Autofluorescent Granules in the Retinal Pigment Epithelium Requires Lysosome Dysfunction

“…The expression of a mutated inactive form of CTSD lead to impaired processing of POS in RPE cells 38,39 and in a mouse model of CLN10 disease, the absence of CTSD increased the accumulation of storage material with age. 45 Nevertheless, different cathepsins and other lysosomal enzymes, such as cysteine proteases and lipases, probably play equally important roles in POS degradation. 4 This point should be addressed further in future studies.…”