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.
Highlights
The neuropathology observed in patients bearing progranulin (GRN) loss-of-function (LOF) mutations is dictated by a gene dosage-dependent effect, with most haploinsufficient individuals developing an early-onset form of frontotemporal dementia (FTD-Human progranulin gene (GRN)) [4, 14]
Central nervous system (CNS) Murine progranulin (Pgrn) expression in 18 month old Murine progranulin gene (Grn)+/+ and GrnR493X/R493X mice was assayed using multiple immunological detection methods, including western blot (Fig. 1a), enzyme-linked immunofluorescent assay (ELISA) (Fig. 1b), and immunofluorescence microscopy (Fig. 1c, d). These results demonstrate that nonsense mutant Pgrn expression is significantly reduced, detecting GrnR493X/R493X global Pgrn CNS expression levels of 14.7% ± 1.7% (ELISA) and 21.7% ± 2.5% relative to Grn+/+ expression levels (Fig. 1a, b)
We found that microglial Pgrn fluorescent intensity was significantly lower in the CA3 and ventral posteromedial (VPM)/VPL of GrnR493X/R493X mice, suggesting that microglial activation in these regions does not result in substantial basal premature termination codon (PTC) readthrough or accumulation of truncated Pgrn-R493X (Fig. 5b, d)
Summary
The neuropathology observed in patients bearing progranulin (GRN) loss-of-function (LOF) mutations is dictated by a gene dosage-dependent effect, with most haploinsufficient individuals developing an early-onset form of frontotemporal dementia (FTD-GRN) [4, 14]. The majority of known neurobiological functions of PGRN have been uncovered through the use of mouse models null for Grn (Grn−/−), partially because preclinical models of Grn haploinsufficiency do not replicate many of the neuropathological hallmarks observed in either FTD-GRN or CLN11. The GrnR493X mouse model was generated to more accurately model FTD-GRN by introducing one of the most common human nonsense mutation leading to FTD (R493X) at the analogous mouse Grn codon (R504X) [29]. Previous characterization of this nonsense mutant Grn model identified several disease phenotypes seen in other Grn−/− models, but lysosomal dysfunction beyond increases in lipofuscin or degeneration of selective neuronal populations have not yet been identified [29]. We sought to comprehensively characterize behavioral and neuropathological phenotypes in aged GrnR493X/R493X mice, which is critical to fully using this model for drug discovery and efficacy testing
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