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C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits

Koppers, Max, Blokhuis, Anna M., Westeneng, Henk-Jan, Terpstra, Margo L., Zundel, Caroline A. C., Vieira de Sá, Renata, Schellevis, Raymond D., Waite, Adrian James, Blake, Derek J, Veldink, Jan H., van den Berg, Leonard H. and Pasterkamp, R. Jeroen 2015. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Annals of Neurology 78 (3) , pp. 426-438. 10.1002/ana.24453

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Abstract

OBJECTIVE: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice. METHODS: We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed. RESULTS: Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival. INTERPRETATION: Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley-Blackwell
ISSN: 0364-5134
Date of Acceptance: 31 May 2015
Last Modified: 10 Jun 2019 09:33
URI: http://orca.cf.ac.uk/id/eprint/80989

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