September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Evaluation of lipofuscin accumulation and retinal degeneration in the mouse model of the Neuronal Ceroid Lipofuscinosis variant CLN6
Author Affiliations & Notes
  • Philipp Guennel
    Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
  • Kirstan Vessey
    Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
  • Alexandra Grubman
    Pathology, University of Melbourne, Melbourne , Victoria, Australia
  • Anthony White
    Pathology, University of Melbourne, Melbourne , Victoria, Australia
  • Erica Fletcher
    Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
  • Footnotes
    Commercial Relationships   Philipp Guennel, None; Kirstan Vessey, None; Alexandra Grubman, None; Anthony White, None; Erica Fletcher, None
  • Footnotes
    Support  National Health and Medical Research Council of Australia (APP 1061419)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2710. doi:
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      Philipp Guennel, Kirstan Vessey, Alexandra Grubman, Anthony White, Erica Fletcher; Evaluation of lipofuscin accumulation and retinal degeneration in the mouse model of the Neuronal Ceroid Lipofuscinosis variant CLN6. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2710.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Autofluorescent intracellular debris, termed lipofuscin, accumulates in all neurons of the Neuronal Ceroid Lipofuscinosis (NCL) variants and leads to visual impairment, as well as mental and motor deficits. Lipofuscin is believed to be responsible for the progressive vision decline in the ocular phenotype of the CLN6nclf mouse model of this disease. The aim of this study was to characterise the development of ocular pathology and the impact of lipofuscin, in the mouse model of late infantile NCL, variant CLN6nclf.

Methods : Eyes of CLN6nclf and C57BL6/J mice were investigated at 1, 2, 4 and 8 months of age. Ocular morphology was assessed by retinal fundus pictures. Gross histology and analysis of retinal layer thickness (N=5) was performed on 1µm sections. Retinal function was studied through electroretinography (N=10). Interactions of microglia and spatial location of lipofuscin was determined by immunohistochemistry and the detection of autofluorescence respectively. Gliosis was investigated by labelling of Müller cells for glial fibrillary acidic protein (GFAP). For statistical analysis, Two-way ANOVA for genotype and age was performed.

Results : Retinal fundus photography showed the presence of abnormal ocular lesions in CLN6nclf mice from 2 months of age. Histological evaluation of the retina demonstrated autofluorescent lipofuscin accumulation within the retinal pigment epithelium (RPE) and retinal neurons. By 8 months CLN6nclf mice showed a significant reduction of the photoreceptor layer (p<0.0001) while inner retinal structure remained intact. At this time, Müller glial cells demonstrated increased gliosis and microglia were activated, especially in the outer retinal layers. Retinal function in CLN6nclf mice decreased in an age dependant manner (p<0.0001) with both photoreceptor (p<0.0001) and inner retinal neuronal (p<0.0001) deficits apparent from 2 months, compared to age matched controls.

Conclusions : Early change in photoreceptor function prior to loss of photoreceptor neurons, in conjunction with accumulation of lipofuscin within the RPE in CLN6nclf mice suggests impairment of the RPE may lead to subsequent visual dysfunction in this mouse model. Showing various age related macular degeneration (AMD) like features, the CLN6nclf mouse model, holds promise as a fast progressing model of this ocular disease.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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