C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

• DOI: 10.1016/j.neuron.2015.10.027
• Publication Date: 2015-12-03T10:15:14Z
• Authors: Jacqueline G. O’R...; Laurent Bogdanik; A.K.M.G. Muhammad; Tania F. Gendron; Kevin J. Kim; Andrew Austin; Janet Cady; Elaine Y. Liu; Jonah Zarrow; Sharday Grant; Ritchie Ho; Shaughn Bell; Sharon Carmona; Megan Simpkinson; Deepti Lall; Kathryn Wu; Lillian Daughrity; Dennis W. Dickson; Matthew B. Harms; Leonard Petrucelli; Edward B. Lee; Cathleen M. Lutz; Robert H. Baloh
• Keywords: 0301 basic medicine; Chromosomes, Artificial, Bacterial; Neuroscience(all); Neuromuscular Junction; 610; Glutamic Acid; Mice, Transgenic; Motor Activity; Mice; 03 medical and health sciences; Medicine and Health Sciences; Animals; Humans; Muscle Strength; Cells, Cultured; Neurons; DNA Repeat Expansion; C9orf72 Protein; Amyotrophic Lateral Sclerosis; Age Factors; Life Sciences; Brain; Proteins; Disease Models, Animal; Frontotemporal Dementia; Psychomotor Performance

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (∼100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.