期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 12, 页码 E2849-E2858出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1722344115
关键词
progranulin; frontotemporal dementia; neurodegeneration; nonsense-mediated mRNA decay; lysosome
资金
- National Institutes of Health Grants [AG023501, GM105718, AG047270, AG047339]
- VA Merit Award [BX002978]
- Bluefield Project postdoctoral fellowship
- Consortium for Frontotemporal Dementia Research
- Gladstone Institutes
- National Center for Research Resources Grant [RR18928]
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 Grn(R493X) knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn(R493X) 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 Grn(R493X) mice and cell lines and in fibroblasts from patients containing the GRN(R493X) 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.
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