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

作者：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 Bauer, Ena C. Whitelaw, Linda Rousseau, Jeannette N. Stankowski, Caroline Stetler, Lillian M. Daughrity, Emilie A. Perkerson, Pamela Desaro, Amelia Johnston, Karen Overstreet, Dieter Edbauer, Rosa Rademakers, Khrista Boylan, Dennis W. Dickson, John Denis Fryer, Leonard Petrucelli · 发表于：Science · 年份：2015 · DOI：10.1126/science.aaa9344 · 被引用次数：411 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Prion Diseases and Protein Misfolding

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.