Abstract
P 084
New mouse model exhibiting early retinal senescence to study age-related maculopathies.
Thomas Claudepierre1, Manuel Simmonutti2, Isabelle Buard3, Serge Picaud2, Robert Maue4, Frank Pfrieger3
1Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Leipzig, Germany; 2Traitement des informations visuelles, INSERM 592, Institut de la Vision, Paris, France; 3CNRS UPR 3212, Institute of Cellular and Integrative Neurosciences (INCI), Strasbourg, France; 4Department of Physiology, Dartmouth Medical School, Hanover, NH, United States
Objective
New animal models that rapidly develop signs of sensescence within the retina are essential for a better understanding of the early steps in various age-related retinal diseases. Here we studied a mouse line that carries a spontaneous mutation in the Niemann Pick Type C 1 (NPC1) gene. NPC1 deficiency leads to impaired lysosomal trafficking and specific neuronal cell death in the central nervous system. Up to now, no retinal analysis has been achieved in those animals even if a visual phenotype has been reported in NPC patients exhibiting similar mutation (Palmer et al., 1985 Arch Ophthalmol).
Methods
We analyzed whether NPC1 deficient mice show pathological changes in the retina, using electroretinogram, ophthalmoscope, immunohistological and ultrastructural analysis
Results
Histochemical and biochemical analysis revealed a perturbed histology in mutant animals with numerous folds of photoreceptors and almost complete absence of outer segments and cones pedicles at the vicinity of the folds. Cholesterol accumulations were detected mostly in the pigmented epithelium, forming basal laminar deposits. Synaptic markers were diminished in synapses underlying cholesterol accumulations. In accordance with histochemical results, electroretinograms revealed a defect in retinal neurotransmission in two months old NPC1 mice. Cholesterol transport was dramatically perturbed: expression of apolipoprotein ApoA1 and ABCA1 transporter were strongly enhanced in NPC1 mouse. Electron microscopy studies revealed dramatic changes in the morphology of the RPE including loss of contact with the Bruch’s membrane, and presence of numerous lysosomal vesicles.
Conclusions
Altogether our results have demonstrate that cholesterol shuttle between glia, neurons, and pigmented epithelium cells is deeply modified in mutant retina and that NPC1 was an unsuspected but essential component of this tripartite dialogue. Two months old Npc1 deficient mice exhibit sign of senescence within the retina, and NPC1 deficiency leads to lysosomal storage disorders within the retina affecting primarily photoreceptors and RPE. NPC1 deficient mice might therefore serve as a model to study the aging aspect in maculopathies, such as age-related macular degeneration.
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