Biochemical, biomarker, and behavioral characterization of theGrn^R493Xmouse model of frontotemporal dementia

Abstract

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, theGrnR493Xmouse 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 homozygousGrnR493Xknockin mice, which includes neuropathological assessment, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygousGrnR493X, we found increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. HeterozygousGrnR493Xmice exhibited more limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits inGrnR493Xmice that mirror those observed in Grn mouse models, as well as impairment in memory and executive function. Overall, theGrnR493Xknockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygousGrnR493Xmice 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 pre-clinical studies that use this and otherGrnmouse models.