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

Academic Article

Abstract

  • © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. 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 virusprogranulin 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 progranulindeficient 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

    Published In

  • Brain  Journal
  • Digital Object Identifier (doi)

    Author List

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

  • 1447
  • End Page

  • 1465
  • Volume

  • 140
  • Issue

  • 5