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A Novel Murine Knock‐in Model for Progranulin‐deficient Frontotemporal Dementia with Nonsense‐mediated mRNA Decay
Author(s) -
Nguyen Andrew D.,
Nguyen Thi A.,
Zhang Jiasheng,
Devireddy Swathi,
Zhou Ping,
Karydas Anna M.,
Xu Xialian,
Miller Bruce L.,
Rigo Frank,
Ferguson Shawn M.,
Huang Eric J.,
Walther Tobias C.,
Farese Robert V.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.807.8
Subject(s) - frontotemporal dementia , nonsense mediated decay , nonsense mutation , knockout mouse , biology , mutation , cancer research , medicine , dementia , genetics , gene , disease , pathology , rna splicing , rna , missense mutation
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 Grn R493X knock‐in 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, 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. The expressed truncated R493X mutant protein was functional in several assays in progranulin‐deficient cells, suggesting that NMD inhibition could be an effective as a therapeutic approach for treating progranulin deficiency caused by the R493X mutation. The Grn R493X mice and associated cell lines provide novel model systems to identify therapies for treating FTD resulting from GRN nonsense mutations. Support or Funding Information This work is supported by National Institutes of Health Grants AG023501 (to R.V.F.) and AG047339 (to A.D.N.), VA Merit Award BX002978 (to E.J.H.), the Consortium for Frontotemporal Dementia Research (to R.V.F., T.C.W., E.J.H., S.M.F., and B.L.M.), and the Gladstone Institutes. T.C.W. is an investigator of the Howard Hughes Medical Institute. The Gladstone Institutes received support from a National Center for Research Resources grant RR18928. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .