Abstract
Loss-of-function mutations in progranulin (GRN) are one of the most common genetic causes of frontotemporal dementia (FTD), a progressive, fatal neurodegenerative disorder with no available disease-modifying treatments. Through haploinsufficiency, these mutations reduce levels of progranulin, a protein that has neurotrophic and anti-inflammatory effects. Increasing progranulin expression from the intact allele is therefore a potential approach for treating individuals with GRN mutations. Based on the well-known effects of physical exercise on other neurotrophic factors, we hypothesized that exercise might increase brain progranulin levels. We tested this hypothesis in progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We housed wild-type and progranulin-insufficient mice in standard cages or cages with exercise wheels for 4 or 7.5 weeks, and then measured brain and plasma progranulin levels. Although exercise modestly increased progranulin in very young (2-month-old) wild-type mice, this effect was limited to the hippocampus. Exercise did not increase brain progranulin mRNA or protein in multiple regions, nor did it increase plasma progranulin, in 4- to 8-month-old wild-type or Grn+/− mice, across multiple experiments and under conditions that increased hippocampal BDNF and neurogenesis. Grn−/−mice were included in the study to test for progranulin-independent benefits of exercise on gliosis. Exercise attenuated cortical microgliosis in 8-month-old Grn−/−mice, consistent with a progranulin-independent, anti-inflammatory effect of exercise. These results suggest that exercise may have some modest, nonspecific benefits for FTD patients with progranulin mutations, but do not support exercise as a strategy to raise progranulin levels.
Highlights
Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder with multiple clinical subtypes and Received November 24, 2014; accepted June 16, 2015; First published June 22, 2015.May/June 2015, 2(3) e0061-14.2015 1–12Loss-of-function mutations in GRN, the progranulin gene, are one of the most common genetic causes of frontotemporal dementia (FTD) and account for 5–10% of all FTD cases (Baker et al, 2006; Cruts et al, 2006; Gass et al, 2006)
We investigated whether physical exercise could increase progranulin levels and ameliorate progranulin deficiency in Grnϩ/Ϫ mice, a model of FTD due to GRN mutations
We found that exercise did not produce sufficient increases in progranulin mRNA or protein levels in hippocampus, frontal cortex, or thalamus of 4- to 8-month-old Grnϩ/Ϫ mice under conditions that were sufficient to increase hippocampal BDNF and activate neurogenesis
Summary
Frontotemporal dementia (FTD) is a devastating neurodegenerative disorder with multiple clinical subtypes and Received November 24, 2014; accepted June 16, 2015; First published June 22, 2015.May/June 2015, 2(3) e0061-14.2015 1–12Loss-of-function mutations in GRN, the progranulin gene, are one of the most common genetic causes of FTD and account for 5–10% of all FTD cases (Baker et al, 2006; Cruts et al, 2006; Gass et al, 2006). Progranulininsufficient mice (Grnϩ/Ϫ and GrnϪ/Ϫ) provide an animal model of progranulin haploinsufficiency and have several phenotypes that may model aspects of FTD. Both Grnϩ/Ϫ and GrnϪ/Ϫ mice develop abnormal behavior and show signs of amygdala dysfunction beginning around 6 months of age (Kayasuga et al, 2007; Yin et al, 2010; Ghoshal et al, 2012; Filiano et al, 2013). GrnϪ/Ϫ, but not Grnϩ/Ϫ mice, develop progressive gliosis, inflammation, and lipofuscinosis in several brain regions that first becomes detectable around 6 –7 months of age and is more strongly elevated by 12 months (Ahmed et al, 2010; Yin et al, 2010; Wils et al, 2012; Filiano et al, 2013; Götzl et al, 2014)
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