Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice
Jonathan Frew, Haakon B. Nygaard
Abstract
Abstract Frontotemporal lobar degeneration (FTLD) causes a spectrum of clinical presentations of frontotemporal dementia (FTD), including progressive changes in behavior, personality, executive function, and language. Up to 20% of familial FTLD cases are caused by progranulin ( GRN ) haploinsufficiency (FTD- GRN ), with one of the most common causal variant being a nonsense mutation at arginine 493 (R493X). Recently, a genetic knockin FTD- GRN mouse model was generated bearing this Grn R493X mutation, at the analogous arginine in murine Grn . Aged, homozygous Grn R493X mice ( Grn R493X/R493X ) have been shown to phenotypically replicate several neuropathological hallmarks previously demonstrated in Grn null mice. We conducted a comprehensive neuropathological and behavioral assessment of 18 month old Grn R493X/R493X mice, observing a striking lysosomal dysfunction and thalamic neurodegeneration not previously described in this model, as well as a male-specific increase in generalized anxiety. These findings provide additional phenotypic markers of pathogenesis in aged Grn R493X/R493X mice that will contribute to better defining mechanisms underlying FTD- GRN , and offer relevant outcome measures for preclinical efficacy testing of novel therapeutics that target nonsense mutations leading to this devastating disease.