| Literature DB >> 26637797 |
Owen M Peters1, Gabriela Toro Cabrera1,2, Helene Tran1, Tania F Gendron3, Jeanne E McKeon1, Jake Metterville1, Alexandra Weiss1, Nicholas Wightman1, Johnny Salameh1, Juyhun Kim4, Huaming Sun2, Kevin B Boylan5, Dennis Dickson3, Zack Kennedy1, Ziqiang Lin1, Yong-Jie Zhang3, Lillian Daughrity3, Chris Jung6, Fen-Biao Gao1, Peter C Sapp1,7, H Robert Horvitz7, Daryl A Bosco1, Solange P Brown4, Pieter de Jong6, Leonard Petrucelli3, Chris Mueller2, Robert H Brown1.
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.Entities:
Keywords: Amyotrophic lateral sclerosis (ALS); C9ORF72; RAN translation; RNA foci; frontotemporal dementia (FTD); microRNA; neurodegeneration; repeat expansions; transgenic mice
Mesh：
Substances：
Year: 2015 PMID： 26637797 PMCID： PMC4828340 DOI： 10.1016/j.neuron.2015.11.018
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173