Neuropathological and behavioral characterization of aged Grn R493X progranulin-deficient frontotemporal dementia knockin mice.

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 mutation, at the analogous arginine in murine Grn. Aged, homozygous Grn mice (Grn) 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 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 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.