Human Molecular Genetics Advance Access published online on May 20, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn156
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Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy
1 Departments of Neurology, Columbia University Medical Center, New York, NY 10032, USA 2 The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA 3 Departments of Surgery, Columbia University Medical Center, New York, NY 10032, USA 4 Departments of Pathology, Columbia University Medical Center, New York, NY 10032, USA 5 Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA 6 Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106. USA
* Corresponding author: Umrao R. Monani Mailing address: 701 W. 168th St., Hammer Health Science Center, Room 511, New York, NY 10032, USA Tel: (212)-342-5132 Fax: (212)-342-4512 E-mail address: um2105{at}columbia.edu
Received February 25, 2008; Revised April 30, 2008; Accepted May 15, 2008
Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the Survival of Motor Neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of reduced SMN protein. In this study, we have used severe and mild SMN2 expressing mouse models of SMA as well as material from human patients to understand the initial stages of neurodegeneration in the human disease. We show that the earliest structural defects appear distally and involve the neuromuscular synapse. Insufficient SMN protein arrests the post-natal development of the neuromuscular junction (NMJ), impairing the maturation of acetylcholine receptor (AChR) clusters into ‘pretzels’. Pre-synaptic defects include poor terminal arborization and intermediate filament aggregates which may serve as a useful biomarker of the disease. These defects are reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. We suggest that SMA might best be described as a neuromuscular junction synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ.
* The authors wish it to be known that, in their opinion, these two authors should be regarded as joint authors.
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