Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice
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Authors
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
Brown, Robert H. Jr.
UMass Chan Affiliations
Horae Gene Therapy CenterDepartment of Pediatrics, Division of Pulmonary and Allergy
Department of Neurology
Document Type
Journal ArticlePublication Date
2015-12-02Keywords
Amyotrophic lateral sclerosis (ALS)C9ORF72
RAN translation
RNA foci
frontotemporal dementia (FTD)
microRNA
neurodegeneration
repeat expansions
transgenic mice
Neurology
Neuroscience and Neurobiology
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Show full item recordAbstract
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.Source
Neuron. 2015 Dec 2;88(5):902-9. doi: 10.1016/j.neuron.2015.11.018. Link to article on publisher's siteDOI
10.1016/j.neuron.2015.11.018Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43760PubMed ID
26637797Notes
Full author list omitted for brevity. For full list of authors see article.
Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.neuron.2015.11.018