Brief communicationSensitivity to neurotoxic stress is not increased in progranulin-deficient mice
Introduction
Progranulin is a pleiotropic protein expressed in multiple tissues and cell types and involved in diverse biological processes. Autosomal dominant loss-of-function mutations in GRN are a major cause of familial frontotemporal lobar degeneration. The mechanism(s) by which GRN deficiency leads to neurodegeneration are not entirely clear. Progranulin is a growth factor in multiple cell types and a stress response factor in fibroblasts and neuroblastoma cell lines. Several lines of evidence indicate that progranulin may play a role in stress-induced cell death in the brain (Guo et al., 2010; Martens et al., 2012; Tao et al., 2012). Progranulin-deficient mice display some behavioral abnormalities and age-dependent neuropathologic changes, but overt neuronal loss has never been reported (Ahmed et al., 2010; Petkau et al., 2012; Yin et al., 2010). We report on the sensitivity of progranulin knockout mice to acute administration of a panel of 4 different neurotoxins. Neither the mechanism of action (excitotoxicity, metabolic stress) nor the specific region targeted (striatum, hippocampus) were associated with differentially induced neurotoxicity in Grn−/− mice. Thus, progranulin deficiency in mice does not affect the response to acute neurotoxin administration based on the methods and outcome measures used in this study.
Section snippets
Methods
Generation of progranulin-deficient mice carrying a gene-trap allele (denoted pFleo allele) was described previously (Petkau et al., 2010). Constitutive progranulin knockout (Grn−/−) mice were generated as described in Supplementary Methods. Four different neurotoxins were administered to separate mixed sex cohorts of 3-month-old Grn+/+ and Grn−/− mice. Intraperitoneal (i.p.) injections of 3-nitropropionic acid (3-NP) were given twice daily for 3 consecutive days for a cumulative dose of 300
Results
Peripheral administration of 3-NP causes selective cell death in the striatum. Grn+/+ and Grn−/− mice were injected with 3-NP and neuronal pathology in the striatum was examined 7 days later. The number of degenerating neurons present in the striatum in 3-NP–treated animals did not differ between genotypes (Fig. 1A). Similarly, lesion volume as measured with FJB staining did not differ significantly between the genotypes (Fig. S1D). The sensitivity of Grn−/− mice to intrastriatal injection of
Discussion
The hypothesis that constitutive progranulin deficiency in mice leads to increased sensitivity of neurons to acute neurotoxic stressors was examined. The data do not indicate any increased sensitivity in progranulin-deficient neurons to 3-NP, QUIN, KA, or PILO. This result is surprising given that progranulin has been shown to be a neuroprotective or neurotrophic factor important for cellular stress responses in the brain in several instances (Guo et al., 2010; Martens et al., 2012; Tao et al.,
Disclosure statement
The authors have no conflicts of interest to disclose. All animal procedures were performed in accordance with University of British Columbia Animal Care Committee guidelines.
Acknowledgements
This work was supported by the Alzheimer Society of Canada (doctoral trainee award to T.P.), and by the Canadian Institute for Health Research (BRL operating grant no. 97857).
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