Title
Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice
UMMS Affiliation
Department of Neurology; Department of Pediatrics, Division of Pulmonary and Allergy; Horae Gene Therapy Center
Publication Date
2015-12-02
Document Type
Article
Disciplines
Neurology | Neuroscience and Neurobiology
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.
Keywords
Amyotrophic lateral sclerosis (ALS), C9ORF72, RAN translation, RNA foci, frontotemporal dementia (FTD), microRNA, neurodegeneration, repeat expansions, transgenic mice
DOI of Published Version
10.1016/j.neuron.2015.11.018
Source
Neuron. 2015 Dec 2;88(5):902-9. doi: 10.1016/j.neuron.2015.11.018. Link to article on publisher's site
Journal/Book/Conference Title
Neuron
Related Resources
PubMed ID
26637797
Repository Citation
Peters, Owen M.; Toro Cabrera, Gabriela; Tran, Helene; McKeon, Jeanne E.; Metterville, Jake P.; Weiss, Alexandra; Wightman, Nicholas; Salameh, Johnny; Sun, Huaming; Kennedy, Zachary; Lin, Ziqiang; Gao, Fen-Biao; Sapp, Peter; Bosco, Daryl; Mueller, Christian; and Brown, Robert H. Jr., "Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice" (2015). Pediatric Publications and Presentations. 72.
https://escholarship.umassmed.edu/peds_pp/72
Comments
Full author list omitted for brevity. For full list of authors see article.