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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.   Supplementary Information  The online version contains supplementary material available at 10.1186/s40478-021-01158-x.

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