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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(2B/-) 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.

Original publication

DOI

10.1016/j.nmd.2011.09.007

Type

Journal article

Journal

Neuromuscul Disord

Publication Date

03/2012

Volume

22

Pages

263 - 276

Keywords

Age Factors, Animals, Animals, Newborn, Axons, Body Weight, Brain, Bungarotoxins, Disease Models, Animal, Gait Disorders, Neurologic, Gene Expression Regulation, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Endplate, Muscle, Skeletal, Muscular Atrophy, Spinal, Nerve Degeneration, Neuromuscular Diseases, Neuromuscular Junction, Phenotype, RNA, Messenger, Reaction Time, Receptors, Cholinergic, Sensation Disorders, Spinal Cord, Survival of Motor Neuron 1 Protein