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Human Molecular Genetics Advance Access originally published online on May 20, 2008
Human Molecular Genetics 2008 17(16):2552-2569; doi:10.1093/hmg/ddn156
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy

Shingo Kariya1,4, Gyu-Hwan Park1,4,{dagger}, Yuka Maeno-Hikichi6,{dagger}, Olga Leykekhman1, Cathleen Lutz5, Marc S. Arkovitz2, Lynn T. Landmesser6 and Umrao R. Monani1,3,4,*

1 Department of Neurology 2 Department of Surgery 3 Department of Pathology 4 Center for Motor Neuron Biology and Disease, Columbia University Medical Center, New York, NY 10032, USA 5 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA 6 Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

* To whom correspondence should be addressed at: Hammer Health Science Center, Room 511, 701 W. 168th Street, New York, NY 10032, USA. Tel: +1 2123425132; Fax: +1 2123424512; Email: 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 NMJ synaptopathy and that one promising means of treating it could involve maintaining function at the NMJ.

{dagger} The authors wish it to be known that, in their opinion, these two authors should be regarded as Joint Authors.


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