Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice
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Human C90RF72.pdf
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Author(s)
Peters, Owen M.
Cabrera, Gabriela Toro
Tran, Helene
Gendron, Tania F.
McKeon, Jeanne E.
Metterville, Jake
Weiss, Alexandra
Wightman, Nicholas
Salameh, Johnny
Kim, Juhyun
Date Issued
December 2015
Journal
Neuron
Publisher
Elsevier
Citation
Peters, Owen M., Gabriela Toro Cabrera, Helene Tran, Tania F. Gendron, Jeanne E. McKeon, Jake Metterville, Alexandra Weiss, et al. “Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice.” Neuron 88, no. 5 (December 2015): 902–909.
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Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
McGovern Institute for Brain Research at MIT
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DOI of Published Version
https://doi.org/10.1016/j.neuron.2015.11.018
