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Yevgeniya Atiskova, Tatyana Danyukova, Elke Becker, Susanne Bartsch, Christian Hagel, Stephan Storch, Udo Bartsch; Retinal degeneration in a mouse model of neuronal ceroid lipofuscinosis type 1 (CLN1). Invest. Ophthalmol. Vis. Sci. 2018;59(9):6073.
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© ARVO (1962-2015); The Authors (2016-present)
Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is an autosomal recessive lysosomal storage disorder caused by mutations in the PPT1 gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures and retinal degeneration. Here, we performed an in depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition.
Immunohistochemical analyses of retinas from PPT1-deficient mice of different ages were performed to determine the onset of retinal degeneration, to analyze the expression levels of various lysosomal proteins, the composition of storage material, reactive astrogliosis and microgliosis, and to quantify the progressive loss of different retinal cell types. In addition, we performed Western blot analyses to quantify the dysregulation of various lysosomal proteins and the accumulation of the major components of the storage material. The ultrastructure of storage material was studied by electron microscopy.
Reactive astrogliosis and elevated expression levels of several lysosomal proteins were observed in 45 days old PPT1-deficient mice, demonstrating an early onset of a retinal pathology in this mutant. The retina of 8 months old PPT1-deficient mice was characterized by a massive astrogliosis and microgliosis, a pronounced upregulation of various lysosomal proteins and an accumulation of Saposin D. The storage material resembled granular osmiophilic deposits at the ultrastructural level. At this advanced stage of the disease, we found a significant loss of cone photoreceptor cells, ganglion cells and retinal interneurons.
The PPT1-deficient mouse displays a complex retinal phenotype that is characterized by an accumulation of storage material, dysregulation of several lysosomal proteins and progressive degeneration of various retinal cell types. Data of this study will serve as a reference for experimental therapeutic strategies aimed at developing and evaluating treatments for retinal degeneration in CLN1 disease.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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