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

Abstract

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.

• Authors: Andrew D Nguyen, Thi A Nguyen, Jiasheng Zhang, Swathi Devireddy, Ping Zhou, Anna M Karydas, Xialian Xu, Bruce L Miller, Frank Rigo, Shawn M Ferguson, Eric J Huang, Tobias C Walther, Robert V Farese Jr
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 12 Pg. E2849-E2858 (03 20 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29511098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 the Author(s). Published by PNAS.

Chemical References

• GRN protein, human
• Granulins
• Grn protein, mouse
• Intercellular Signaling Peptides and Proteins
• Oligonucleotides, Antisense
• Progranulins
• RNA, Messenger

Topics

• Animals
• Disease Models, Animal
• Fibroblasts (drug effects)
• Frontotemporal Dementia (etiology, genetics)
• Gene Knock-In Techniques
• Granulins
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Lysosomes (genetics, metabolism)
• Mice, Inbred C57BL
• Mutation
• Nonsense Mediated mRNA Decay (drug effects)
• Oligonucleotides, Antisense (pharmacology)
• Progranulins
• RNA, Messenger