title: Progressive retinal degeneration and accumulation of autofluorescent lipopigments in Progranulin deficient mice.
abstract: Prior investigations have shown that patients with neuronal ceroid lipofuscinosis (NCL) develop neurodegeneration characterized by vision loss, motor dysfunction, seizures, and often early death. Neuropathological analysis of patients with NCL shows accumulation of intracellular autofluorescent storage material, lipopigment, throughout neurons in the central nervous system including in the retina. A recent study of a sibling pair with adult onset NCL and retinal degeneration showed linkage to the region of the progranulin (GRN) locus and a homozygous mutation was demonstrated in GRN. In particular, the sibling pair with a mutation in GRN developed retinal degeneration and optic atrophy. This locus for this form of adult onset neuronal ceroid lipofuscinosis was designated neuronal ceroid lipofuscinosis-11 (CLN11). Based on these clinical observations, we wished to determine whether Grn-null mice develop accumulation of autofluorescent particles and retinal degeneration. Retinas of both wild-type and Progranulin deficient mice were examined by immunostaining and autofluorescence. Accumulation of autofluorescent material was present in Progranulin deficient mice at 12 months. Degeneration of multiple classes of neurons including photoreceptors and retinal ganglion cells was noted in mice at 12 and 18 months. Our data shows that Grn(-/-) mice develop degenerative pathology similar to features of human CLN11.
authors.affiliation: Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: brian_hafler@meei.harvard.edu.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Hafler
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Zoe A
authors.initials: ZA
authors.lastname: Klein
authors.affiliation: Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT 06510, USA; Departments of Cellular and Molecular Physiology and Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Jimmy Zhou
authors.affiliation: Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004596:Electroretinography; D000077155:Granulins; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009472:Neuronal Ceroid-Lipofuscinoses; D061848:Optical Imaging; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology / Q000502:physiology; D000077153:Progranulins; D012162:Retinal Degeneration / Q000473:pathology / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: Autofluorescent storage material; Neurodegeneration; Neuronal ceroid lipofuscinosis; Progranulin