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

Owen M. Peters, Gabriela Toro Cabrera, Helene Tran, Tania F. Gendron, Jeanne E. McKeon, Jake Metterville, Alexandra Weiss, Nicholas Wightman, Johnny Salameh, Juhyun Kim, Huaming Sun, Kevin B. Boylan, Dennis Dickson, Zachary Kennedy, Ziqiang Lin, Yong Jie Zhang, Lillian Daughrity, Chris Jung, Fen Biao Gao, Peter C. SappH. Robert Horvitz, Daryl A. Bosco, Solange P. Brown, Pieter de Jong, Leonard Petrucelli, Christian Mueller, Robert H. Brown

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)902-909
Number of pages8
JournalNeuron
Volume88
Issue number5
DOIs
StatePublished - Dec 2 2015

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Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • C9ORF72
  • Frontotemporal dementia (FTD)
  • MicroRNA
  • Neurodegeneration
  • RAN translation
  • RNA foci
  • Repeat expansions
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Peters, O. M., Cabrera, G. T., Tran, H., Gendron, T. F., McKeon, J. E., Metterville, J., Weiss, A., Wightman, N., Salameh, J., Kim, J., Sun, H., Boylan, K. B., Dickson, D., Kennedy, Z., Lin, Z., Zhang, Y. J., Daughrity, L., Jung, C., Gao, F. B., ... Brown, R. H. (2015). Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron, 88(5), 902-909. https://doi.org/10.1016/j.neuron.2015.11.018