Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice

A non-coding hexanucleotide repeat expansion in the C9ORF72 gene is the most common mutation associated with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To investigate the pathological role of C9ORF72 in these diseases, we generated a line of mice carrying a bacterial artificial chromosome containing exons 1 to 6 of the human C9ORF72 gene with approximately 500 repeats of the GGGGCC motif. The mice showed no overt behavioral phenotype but recapitulated distinctive histopathological features of C9ORF72 ALS/FTD, including sense and antisense intranuclear RNA foci and poly(glycine-proline) dipeptide repeat proteins. Finally, using an artificial microRNA that targets human C9ORF72 in cultures of primary cortical neurons from the C9BAC mice, we have attenuated expression of the C9BAC transgene and the poly(GP) dipeptides. The C9ORF72 BAC transgenic mice will be a valuable tool in the study of ALS/FTD pathobiology and therapy. •Mouse model expressing ALS/FTD associated C9ORF72 hexanucleotide repeat expansion•Formation of sense and antisense C9ORF72 RNA transcript foci•Dipeptide repeat proteins produced by repeat-associated non-ATG translation•Formation of cytoplasmic inclusions containing dipeptide repeat proteins Peters et al. report that transgenic mice expressing ALS/FTD-associated C9ORF72 hexanucleotide expansions develop histopathological features of c9ALS/FTD (RNA foci and aggregates of non-ATG translated dipeptides) but not motor neuron disease. These features are attenuated in vitro by anti-C9ORF72 microRNA.