Fig. 2.

Phenotype of Grn^R493X/R493X mice recapitulates features of global knockout mice. (A and B) Grn^R493X/R493X mice exhibit age-dependent microgliosis. (A) Immunostaining of Iba1 in the thalamus. Arrowheads indicate selected Iba1⁺ cells. (B) Quantification of Iba1⁺ microglial density in 12-mo-old mice, n = 3–4 mice per genotype. (C and D) Increased levels of total (C) and phosphorylated (D) TDP-43 in the cytoplasm of thalamic neurons of 12-mo-old Grn^R493X/R493X and Grn^−/− mice. Arrowheads indicate cytoplasmic accumulation of TDP-43. (Scale bars, 20 μm.) (E and F) Grn^R493X/R493X mice exhibit age-dependent reduction of synaptic density. (E) Immunostaining of synaptophysin in the thalamus of 13-mo-old mice. (Scale bar, 10 μm.) (F) Quantification of synaptophysin density, n = 3–4 mice per genotype at each age. (G and H) Grn^R493X/R493X mice have increased lipofuscin in the brain. (G) Images of autofluorescent lipofuscin (green channel) in the thalamus of 19-mo-old mice. (Scale bar, 10 μm.) (H) Quantification of autofluorescence. (I–K) Grn^R493X/R493X mice have increased skin lesions resulting in decreased survival. (I) Skin lesions in 16-mo old mice. (I and J) Kaplan–Meier curves for skin lesion onset (J) and survival (K) in Grn^+/+ (gray curves) and Grn^R493X/R493X (blue curves) littermate mice. For comparison, curves for Grn^+/+ (purple curves) and Grn^−/− (green curves) littermate mice are also shown. Data are presented as mean ± SD; *P < 0.05, **P < 0.01, ***P < 0.001, as determined by Student’s t test (B, F, and H), Long-rank (Mantel–Cox) test (J and K). n.s., not significant; SPH, synaptophysin.