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. 2019 Dec 23;7:218. doi: 10.1186/s40478-019-0872-6

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© The Author(s). 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Fig. 7 — Grn^−/− Mice Have GCase Activity Deficits That Are Corrected by Restoration of Progranulin with an AAV Vector. Frontal cortical lysates from 7 to 10 month-old wild-type, Grn^+/−_, and Grn^−/− littermates were analyzed for activity of GSL-metabolizing enzymes. A simplified diagram of ganglioside metabolism, with a summary of observed phenotypes in Grn^−/− mice is shown in a. Lipids are shown in black, with the enzymes that metabolize each lipid shown in blue. GM1, 2, and 3 = GM1, 2, and 3 ganglioside, β-Gal = β-galactosidase, β-Hex = β-Hexosaminidase, HexA = β-Hexosaminidase A, GLA = α-galactosidase A, GCase = β-glucocerebrosidase, Neu = neuraminidase (activity not measured in this study). b–f, At this age, Grn^−/− mice exhibited significant increases in activity of β-Gal (b, ANOVA, p = 0.0024), β-Hex (c, ANOVA, p < 0.0001), HexA (d, ANOVA, p < 0.0001), and GLA (e, ANOVA, p < 0.0001). However, Grn^−/− mice exhibited a decrease in GCase activity (f, ANOVA, p = 0.0099). n = 6–24 per genotype. * = p < 0.05 ** = p < 0.1, **** = p < 0.0001 by Dunnett’s post-hoc test. g, Analysis of ventral striatum samples from a cohort of Grn^−/− mice treated with AAV-GFP or AAV-progranulin in the medial prefrontal cortex revealed that restoring progranulin to Grn^−/− mice normalized GCase deficits (ANOVA genotype x treatment interaction, p = 0.0122), but that AAV-Grn reduced GCase activity in wild-type mice. h, Analysis of multiple brain regions from a second group of AAV-treated mice produced similar results, (RM ANOVA, genotype x virus x brain region, p = 0.042). Subsequent tests of the effects of virus within genotype confirmed the opposite effects of AAV-Grn in each genotype. In wild-type mice, AAV-Grn reduced GCase activity (RM ANOVA effect of virus, p = 0.0088), but in Grn^−/− mice, AAV-Grn increased GCase activity to near wild-type levels (RM ANOVA effect of virus, p = 0.0072). * = p < 0.05 and **** = p < 0.0001 by Sidak’s post-hoc test. n = 8–11 mice per group in g, with 4 uninjected Grn^−/− mice included as a reference, and 4–6 mice per group in h. β-Gal = β-galactosidase, β-Hex = β-Hexosaminidase, HexA = β-Hexosaminidase A, GLA = α-galactosidase A, GCase = β-glucocerebrosidase, Neu = neuraminidase (activity not measured in this study)