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C 9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits
Author(s) -
Koppers Max,
Blokhuis Anna M.,
Westeneng HenkJan,
Terpstra Margo L.,
Zundel Caroline A. C.,
Vieira de Sá Renata,
Schellevis Raymond D.,
Waite Adrian J.,
Blake Derek J.,
Veldink Jan H.,
van den Berg Leonard H.,
Pasterkamp R. Jeroen
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24453
Subject(s) - amyotrophic lateral sclerosis , c9orf72 , conditional gene knockout , motor neuron , neuroscience , gliosis , knockout mouse , lower motor neuron , biology , medicine , pathology , phenotype , disease , frontotemporal dementia , genetics , dementia , receptor , spinal cord , gene
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. Ann Neurol 2015;78:426–438