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Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2849-E2858. doi: 10.1073/pnas.1722344115. Epub 2018 Mar 6.

Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay.

Nguyen AD1,2, Nguyen TA1,2, Zhang J3,4, Devireddy S5,6, Zhou P7, Karydas AM8, Xu X7, Miller BL8,9, Rigo F10, Ferguson SM5,6,9, Huang EJ3,4,9, Walther TC11,2,9,12,13, Farese RV Jr11,2,9,12.

Author information

Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Department of Pathology, University of California, San Francisco, CA 94143.
Pathology Service 113B, VA Medical Center, San Francisco, CA 94121.
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510.
Program in Cellular Neuroscience, Neurodegeneration, and Repair, Yale University School of Medicine, New Haven, CT 06510.
Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA 94158.
Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158.
Consortium for Frontotemporal Dementia Research, San Francisco, CA 94107.
Neuroscience Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA 92010.
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115;
Broad Institute, Cambridge, MA 02142.
Howard Hughes Medical Institute, Boston, MA 02115.


Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because 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 knockin 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, hyperinflammatory 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 murine model for in vivo testing of NMD inhibition or other therapies as potential approaches for treating progranulin deficiency caused by the R493X mutation.


frontotemporal dementia; lysosome; neurodegeneration; nonsense-mediated mRNA decay; progranulin

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