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

摘要: 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 vivo is, however, incomplete. Here we determined the effect of C9orf72 mice. Methods We generated analyzed a conditional knockout mouse model. C9orf72fl/fl mice were crossed with Nestin-Cre to selectively remove from neurons glial cells. Immunohistochemistry was performed study motor neuromuscular integrity, as well several pathological hallmarks ALS, such gliosis TDP-43 mislocalization. In addition, function survival assessed. Results Neural-specific ablation resulted significantly reduced body weight but did not induce neuron degeneration, defects function, or altered survival. Interpretation Our data suggest that loss-of-function, by itself, is insufficient disease. These results may important implications for development therapeutic strategies C9orf72-associated ALS. Ann Neurol 2015;78:426–438