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Brian Hafler, Zoe Klein, Stephen Strittmatter; Progranulin Mutant Mice Exhibit Accumulation of Intraneuronal Lipofuscin Aggregates in the Retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6115.
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Patients lacking progranulin develop neuronal ceroid lipofuscinosis, a neurodegenerative lysosomal disorder characterized by abnormal lipofuscin accumulation. Previous investigations have shown that mice lacking progranulin, a secreted glycoprotein encoded by the granulin (GRN) gene, develop abnormal intraneuronal lipofuscin accumulation in the brain. To determine if progranulin mutant mice have a similar phenotype in the retina as observed in humans with mutations in the progranulin gene, GRN-/- retinas were examined for lipofuscin accumulation.
In order to address whether the age-accelerated lipofuscin accumulation in the brains of GRN /- mice was present in the retina, we examined the retinas of progranulin deficient mice. The generation of GRN-/- mice has been described previously (Kayasuga et al., 1997). GRN -/- genotype was detected using PCR with primers directed against GRN and western blot for progranulin protein. GRN-/- mice were examined for lipofuscin using confocal microscopy autofluorescence.
As expected, GRN-/- mice lacked progranulin compared to controls using western blot. Given than humans deficient for progranulin develop retinal dystrophy, GRN-/- mice were examined for lipofuscin in 12 month old mice. Retinas from GRN-/- mice were examined using autofluorescence, and interestingly, there was intracellular accumulation of highly autofluorescent lipofuscin material in neurons as compared to GRN+/+ mice.
These data indicate that GRN-/- mice exhibit an accumulation of intraneuronal autofluorescent lipofuscin aggregates. As humans with the neurodegenerative disease neuronal ceroid lipofuscinosis linked to progranulin gene mutations on chromosome 17 have excessive accumulation of lipofuscin in the retina, this study is, to our knowledge, is the first example demonstrating a similar retinal phenotype of GRN-/- mice providing a new model to investigate the retinal pathology found in this disorder.
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