C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD (P4.001)

OBJECTIVE: To report a novel transgenic mouse model of ALS/FTD from hexanucleotide expansion mutations in the C9orf72 gene. BACKGROUND: Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the first intron of the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. DESIGN/METHODS: We generated 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 (~100-1000 repeats; C9-BACexp). Mice were analyzed pathologically and behaviorally, and cortical cells were cultured. RESULTS: C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat associated non-ATG (RAN) translated dipeptides. RAN dipeptides and RNA foci were generated at levels similar to those observed in patient tissues, and could be suppressed by antisense oligonucleotides targeting human C9orf72 in cortical cultures from the mice. Nucleolin distribution was altered supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. CONCLUSIONS: Despite early and widespread production of RNA foci and RAN dipeptide inclusions in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptide production occur presymptomatically in humans and may not be sufficient to drive cell death in the absence of overexpression or other stressors. Disclosure: Dr. Baloh has nothing to disclose. Dr. O9Rourke has nothing to disclose. Dr. Bell has nothing to disclose. Dr. Bogdonik has nothing to disclose. Dr. Muhammad has nothing to disclose. Dr. Gendron has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Austin has nothing to disclose. Dr. Cady has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Zarrow has nothing to disclose. Dr. Grant has nothing to disclose. Dr. Ho has nothing to disclose. Dr. Carmona has nothing to disclose. Dr. Simpkinson has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Daughrity has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Harms has received personal compensation for activities as an expert witness testimony. Dr. Harms has received research support from Merck, Isis Pharmaceuticals, and Biogen Idec. Dr. Petrucelli has nothing to disclose. Dr. Lutz has nothing to disclose.