Journal
NEUROMUSCULAR DISORDERS
Volume 22, Issue 3, Pages 263-276Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2011.09.007
Keywords
Spinal muscular atrophy; Mouse model; Neuromuscular junction; Smn threshold; Motor neuron; Selective vulnerability
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Funding
- Canadian Institutes of Health Research (CIHR)
- Muscular Dystrophy Association
- Multiple Sclerosis Society
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Spinal muscular atrophy (SMA) is caused by mutations/deletions within the SMN1 gene and characterized by loss of lower motor neurons and skeletal muscle atrophy. SMA is clinically heterogeneous, with disease ranging from severe to mild. Here, we identify a critical threshold of Smn that dictates onset of SMA in the intermediate Smn(2B/-) mouse model. With about 15% normal level of Smn protein, Smn(2/B-) mice display reduced body weight, motor neuron loss and motor defects. Importantly, these mice are phenotype-free until P10 with a median life expectancy of 28 days. They show neuromuscular junction (NMJ) pathology with an inter-muscular differential vulnerability and an association between pre- and post-synaptic defects. Our work suggests that increasing Smn protein levels only minimally could be of significant benefit since Smn(2B/2B) mice are phenotypically normal. Further, the finding that NMJ pathology varies between severe and intermediate SMA mouse models, suggests that future therapies be adapted to the severity of SMA. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.
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