C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

Jeannie Chew, Tania F. Gendron, Mercedes Prudencio, Hiroki Sasaguri, Yong Jie Zhang, Monica Castanedes-Casey, Chris W. Lee, Karen Jansen-West, Aishe Kurti, Melissa E. Murray, Kevin F. Bieniek, Peter O. Bauer, Ena C. Whitelaw, Linda Rousseau, Jeannette N. Stankowski, Caroline Stetler, Lillian M. Daughrity, Emilie A. Perkerson, Pamela Desaro, Amelia JohnstonKaren Overstreet, Dieter Edbauer, Rosa Rademakers, Kevin B. Boylan, Dennis W. Dickson, John D. Fryer, Leonard Petrucelli

Research output: Contribution to journalArticle

192 Scopus citations

Abstract

The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.

Original languageEnglish (US)
Pages (from-to)1151-1154
Number of pages4
JournalScience
Volume348
Issue number6239
DOIs
StatePublished - Jun 5 2015
Externally publishedYes

ASJC Scopus subject areas

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    Chew, J., Gendron, T. F., Prudencio, M., Sasaguri, H., Zhang, Y. J., Castanedes-Casey, M., Lee, C. W., Jansen-West, K., Kurti, A., Murray, M. E., Bieniek, K. F., Bauer, P. O., Whitelaw, E. C., Rousseau, L., Stankowski, J. N., Stetler, C., Daughrity, L. M., Perkerson, E. A., Desaro, P., ... Petrucelli, L. (2015). C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science, 348(6239), 1151-1154. https://doi.org/10.1126/science.aaa9344