title: Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia.
abstract: Loss-of-function mutations in progranulin (GRN), a secreted glycoprotein expressed by neurons and microglia, are a common autosomal dominant cause of frontotemporal dementia, a neurodegenerative disease commonly characterized by disrupted social and emotional behaviour. GRN mutations are thought to cause frontotemporal dementia through progranulin haploinsufficiency, therefore, boosting progranulin expression from the intact allele is a rational treatment strategy. However, this approach has not been tested in an animal model of frontotemporal dementia and it is unclear if boosting progranulin could correct pre-existing deficits. Here, we show that adeno-associated virus-driven expression of progranulin in the medial prefrontal cortex reverses social dominance deficits in Grn+/- mice, an animal model of frontotemporal dementia due to GRN mutations. Adeno-associated virus-progranulin also corrected lysosomal abnormalities in Grn+/- mice. The adeno-associated virus-progranulin vector only transduced neurons, suggesting that restoring neuronal progranulin is sufficient to correct deficits in Grn+/- mice. To further test the role of neuronal progranulin in the development of frontotemporal dementia-related deficits, we generated two neuronal progranulin-deficient mouse lines using CaMKII-Cre and Nestin-Cre. Measuring progranulin levels in these lines indicated that most brain progranulin is derived from neurons. Both neuronal progranulin-deficient lines developed social dominance deficits similar to those in global Grn+/- mice, showing that neuronal progranulin deficiency is sufficient to disrupt social behaviour. These data support the concept of progranulin-boosting therapies for frontotemporal dementia and highlight an important role for neuron-derived progranulin in maintaining normal social function.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Filiano
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Unger
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Allen H
authors.initials: AH
authors.lastname: Young
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, Alzheimer's Disease Center, and Evelyn F. McKnight Brain Institute, Departments of Neurology and Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D003213:Conditioning, Psychological; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D057180:Frontotemporal Dementia / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D005822:Genetic Vectors; D000077155:Granulins; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D000077153:Progranulins; D012919:Social Behavior; D012930:Social Dominance
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D064231:Nestin; D000077153:Progranulins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: FTD; dementia; experimental models; gene therapy; progranulin