Mice deficient in the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) display a complex retinal phenotype

Yevgeniya Atiskova,Tatyana Danyukova,Stephan Storch,Udo Bartsch,Elke Becker,Susanne Bartsch,Christian Hagel

doi:10.1038/s41598-019-50726-8

Yevgeniya Atiskova, Tatyana Danyukova + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-50726-8

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Abstract

Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). CLN1 patients suffer from brain atrophy, mental and motor retardation, seizures, and retinal degeneration ultimately resulting in blindness. Here, we performed an in-depth analysis of the retinal phenotype of a PPT1-deficient mouse, an animal model of this condition. Reactive astrogliosis and microgliosis were evident in mutant retinas prior to the onset of retinal cell loss. Progressive accumulation of storage material, a pronounced dysregulation of various lysosomal proteins, and accumulation of sequestosome/p62-positive aggregates in the inner nuclear layer also preceded retinal degeneration. At advanced stages of the disease, the mutant retina was characterized by a significant loss of ganglion cells, rod and cone photoreceptor cells, and rod and cone bipolar cells. Results demonstrate that PPT1 dysfunction results in early-onset pathological alterations in the mutant retina, followed by a progressive degeneration of various retinal cell types at relatively late stages of the disease. Data will serve as a reference for future work aimed at developing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease.

Highlights

Neuronal ceroid lipofuscinosis (NCL) comprise a genetically and clinically heterogeneous group of lysosomal storage disorders that is characterized by an intracellular accumulation of autofluorescent storage material, progressive neurodegeneration and premature death
To determine the onset of the retinal pathology in the Ppt[1] ko mouse, we analyzed the expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (IBA1) and cluster of differentiation 68 (CD68) in central retinal sections of mutant and wild-type mice at different ages
In Ppt[1] ko retinas, in comparison, the number of GFAP-positive Müller cells was significantly increased at P45, P112 and P240 when compared with age-matched control retinas (Fig. 1b–d, Supplementary Fig. 1a; p < 0.001 for all comparisons; two-way ANOVA followed by a Bonferroni post-hoc test)

Summary

Introduction

Neuronal ceroid lipofuscinosis (NCL) comprise a genetically and clinically heterogeneous group of lysosomal storage disorders that is characterized by an intracellular accumulation of autofluorescent storage material, progressive neurodegeneration and premature death. Epileptic seizures usually occur at advanced stages of the disease, and patients die at about 10 years of age[20,21] In addition to this most prevalent CLN1 disease ‘classic infantile NCL’ (INCL) variant, patients harboring mutations in the PPT1 gene might develop first clinical symptoms later in life, and present with a more slowly progressing late-infantile, juvenile or adult onset NCL22–28. CLN1 patients with a later onset of the disease presented with night blindness and moderate visual impairment as juveniles, resulting in progressive vision loss and extinguished ERGs at later ages[23,27,28]. Results of the present study will serve as a reference for future work aimed at establishing therapeutic strategies for the treatment of retinal degeneration in CLN1 disease

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