Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Arrant, AE; Filiano, AJ; Unger, DE; Young, AH; Roberson, ED

Published Date

  • May 1, 2017

Published In

Volume / Issue

  • 140 / 5

Start / End Page

  • 1447 - 1465

PubMed ID

  • 28379303

Pubmed Central ID

  • PMC5965303

Electronic International Standard Serial Number (EISSN)

  • 1460-2156

Digital Object Identifier (DOI)

  • 10.1093/brain/awx060


  • eng

Conference Location

  • England