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

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 GrnR493X mutation, at the analogous arginine in murine Grn. Aged, homozygous GrnR493X mice (GrnR493X/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 GrnR493X/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 GrnR493X/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.

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

“…Heterozygous Grn +/R493X mice have similar phenotypes to Grn +/mice, and homozygous Grn R493X/R493X mice have similar phenotypes to Grn -/mice. Like Grn -/mice, Grn R493X/R493X mice exhibit age-dependent thalamic microgliosis and lipofuscinosis as well as compulsive grooming and reduced survival relative to wild-type control mice [126,127]. Also, like Grn -/mice, Grn R493X/R493X mice have age-dependent accumulation of ganglioside species mono-sialylated GM1 and di-sialylated GD-3 in areas of the cortex, further supporting the idea that progranulin deficiency impairs sphingolipid degradation.…”

Biochemical, biomarker, and behavioral characterization of theGrnR493Xmouse model of frontotemporal dementia

“…For the Grn R493X mouse model, we previously reported age-dependent microgliosis in the thalamus of 12-month-old homozygous mice, as determined by quantification of Iba1 + cells after immunohistochemistry [28]. Additionally, Frew and Nygaard reported increased microgliosis and astrogliosis in 18-month-old homozygous mice by immunostaining [37]. Here, we report increased expression of the microglia marker Iba1 and astrocyte marker GFAP in the cortex that is apparent in homozygous mice by 12 months of age (Fig.…”

“…Additional studies are warranted, including measurements of C1qa and C3 levels in the CSF. Our behavioral studies were limited to male mice at 11 months of age; additional studies in female mice are necessary to address possible sex-specific phenotypes, which have been noted in the Grn knockout and Grn R493X mouse models [24,26,37,61].…”

“…Homozygous Grn knockout and knockin mice exhibit signs of lysosomal impairment, including lipofuscin accumulation, NCL-like lysosomal storage material by electron microscopy, and upregulation of lysosomal genes in the brain which is likely to compensate for the lysosomal impairment [28][29][30][31][32][33][34]. Homozygous Grn knockout and knockin mice also show age-dependent neuroinflammation and cytoplasmic accumulation of phosphorylated TDP-43 [25,27,28,32,[34][35][36][37]. Additionally, Grn knockout and Grn R493X knockin mice exhibit deficits in social and emotional behavior, including decreased sociability, age-dependent changes in social dominance, increased anxiety, and increased obsessive-compulsive behaviors [28,[35][36][37][38][39][40].…”

The Advance on Frontotemporal Dementia (FTD)’s Neuropathology and Molecular Genetics

“…GRN carriers usually present with FTD-TDP-1 pathology, and most patients have bvFTD clinical phenotype. Occasionally, PPA patients were also found in these familial cases [ 37 , 38 ].…”