A novel murine knock-in model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay Andrew D. Nguyen1,2,3, Thi A. Nguyen1,2, Jiasheng Zhang4,5, Swathi Devireddy6, Ping Zhou7, Anna M. Karydas4, Xialian Xu7, Bruce L. Miller4,8, Frank Rigo9, Shawn M. Ferguson6,8, Eric J. Huang4,5,8, Tobias C. Walther1,2,8,10,11, and Robert V. Farese, Jr.1,2,8,10 1Harvard T.H. Chan School of Public Health, 2Harvard Medical School, 3Saint Louis University School of Medicine, 4University of California, San Francisco, 5VA Medical Center, 6Yale University School of Medicine, 7Gladstone Institute of Cardiovascular Disease, 8Consortium for Frontotemporal Dementia Research, 9Ionis Pharmaceuticals, 10Broad Institute, 11Howard Hughes Medical Institute
Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Since many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized GrnR493X knock-in mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous GrnR493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyper-inflammatory macrophages, excessive grooming behavior, and reduced survival. Inhibition of nonsense-mediated mRNA decay (NMD) by genetic, pharmacological, or antisense oligonucleotide-based approaches showed that NMD contributes to the reduced mRNA levels in GrnR493X mice and cell lines and in fibroblasts from patients containing the GRNR493X mutation. Moreover, the expressed truncated R493X mutant protein was functional in several assays in progranulin-deficient cells. Together, these findings establish a new murine model for in vivo testing of NMD inhibition or other therapies as a potential approaches for treating progranulin deficiency caused by the R493X mutation.
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