title: Lack of Niemann-Pick type C1 induces age-related degeneration in the mouse retina.
abstract: Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disease and caused by mutations in Npc1 or Npc2, which mediate cooperatively the egress of cholesterol from lysosomes. The disease entails progressive neurodegeneration, whose cause is poorly understood. Here, we report that Npc1 is distributed in distinct layers of the mouse retina and that its deficiency causes striking retinal degeneration in 2-month-old mice with signs of age-related maculopathies. This includes impaired visual function, accumulation of lipofuscin in the retinal pigment epithelium layer, degeneration of photoreceptor outer segments, disruption of synaptic layers and an increase in autophagy markers in the ganglion cell layer. Moreover, the lack of Npc1 results in the upregulation of proteins that mediate cellular cholesterol release in the retina. Our findings suggest that Npc1 is required for normal retinal function and that its absence may serve as model to study age-related degeneration of the retina.
authors.affiliation: CNRS UPR 3212, University of Strasbourg, Institute of Cellular and Integrative Neurosciences (INCI), 5, rue Blaise Pascal, F-67084 Strasbourg, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Claudepierre
authors.forename: Michel
authors.initials: M
authors.lastname: Paques
authors.forename: Manuel
authors.initials: M
authors.lastname: Simonutti
authors.forename: Isabelle
authors.initials: I
authors.lastname: Buard
authors.forename: Jose
authors.initials: J
authors.lastname: Sahel
authors.forename: Robert A
authors.initials: RA
authors.lastname: Maue
authors.forename: Serge
authors.initials: S
authors.lastname: Picaud
authors.forename: Frank W
authors.initials: FW
authors.lastname: Pfrieger
mesh_terms: D000818:Animals; D001343:Autophagy; D002784:Cholesterol / Q000378:metabolism; D004596:Electroretinography; D047908:Intracellular Signaling Peptides and Proteins; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000166:cytology / Q000378:metabolism / Q000473:pathology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol