title: Core neuropathological abnormalities in progranulin-deficient mice are penetrant on multiple genetic backgrounds.
abstract: Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal lobar degeneration (FTLD). A high degree of heterogeneity in the age-of-onset, duration of disease, and clinical presentation of FTLD, even among families carrying the same GRN mutation, suggests that additional modifying genes may be important to pathogenesis. Progranulin-knockout mice display subtle behavioral abnormalities and progressive neuropathological changes, as well as altered dendritic morphology and synaptic deficits in the hippocampus. In this study we evaluated multiple neuropathological endpoints in aged progranulin knockout mice and their wild-type littermates on two different genetic backgrounds: C57Bl/6 and 129/SvImJ. We find that in most brain regions, both strains are susceptible to progranulin-mediated neuropathological phenotypes, including astrogliosis, microgliosis, and highly accelerated deposition of the aging pigment lipofuscin. Neuroinflammation due to progranulin deficiency is exaggerated in the B6 strain and present, but less pronounced, in the 129 strain. Differences between the strains in hippocampal neuron counts and neuronal morphology suggest a complex role for progranulin in the hippocampus. We conclude that core progranulin-mediated neurodegenerative phenotypes are penetrant on multiple inbred mouse strains, but that genetic background modulates progranulin's role in neuroinflammation and hippocampal biology.
authors.affiliation: Center for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: T L
authors.initials: TL
authors.lastname: Petkau
authors.affiliation: Center for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Hill
authors.affiliation: Center for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Division of Neurology, Department of Medicine, University of British Columbia Hospital, S192, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: bleavitt@cmmt.ubc.ca.
authors.forename: B R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D000374:Aggression / Q000502:physiology; D000818:Animals; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005911:Gliosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D018782:Maze Learning / Q000502:physiology; D057507:Mice, 129 Strain / Q000502:physiology; D008810:Mice, Inbred C57BL / Q000502:physiology; D018345:Mice, Knockout / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology; D009474:Neurons / Q000473:pathology; D009929:Organ Size; D000077153:Progranulins; D021641:Recognition, Psychology / Q000502:physiology; D012727:Sex Characteristics; D013045:Species Specificity; D016019:Survival Analysis
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins
keywords: frontotemporal lobar degeneration; genetic background; neuropathology; progranulin; progranulin-knockout mice