Biochemical, biomarker, and behavioral characterization of the Grn(R493X) mouse model of frontotemporal dementia

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the Grn(R493X) mouse model has not been characterized completely. Additionally, while homozygous Grn mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in depth characterization of heterozygous and homozygous Grn(R493X) knockin mice, which includes neuropathological assessment, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous Grn(R493X) mice, we found increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous Grn(R493X) mice exhibited more limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in Grn(R493X) mice that mirror those observed in Grn mouse models, as well as impairment in memory and executive function. Overall, the Grn(R493X) knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous Grn(R493X) mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform preclinical studies that use this and other Grn mouse models.