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Neuron. 2015 Dec 2;88(5):902-909. doi: 10.1016/j.neuron.2015.11.018.

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

Author information

1
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
2
Department of Pediatrics and Gene Therapy Center University of Massachusetts Medical School, Worcester, MA 01655, USA.
3
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Rd., Jacksonville, FL 32224, USA.
4
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205.
5
Department of Neurology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
6
Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, California 94609.
7
Department of Biology, and McGovern Institute for Brain Research, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, MA 02139, H.R.H. is an Investigator of the Howard Hughes Medical Institute.
#
Contributed equally

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

PMID:
26637797
PMCID:
PMC4828340
DOI:
10.1016/j.neuron.2015.11.018
[Indexed for MEDLINE]
Free PMC Article

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