Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy.
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.
Kariya
Shingo
S
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA.
Park
Gyu-Hwan
GH
Maeno-Hikichi
Yuka
Y
Leykekhman
Olga
O
Lutz
Cathleen
C
Arkovitz
Marc S
MS
Landmesser
Lynn T
LT
Monani
Umrao R
UR
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000737:chemistry / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D055540:Survival of Motor Neuron 2 Protein; D009435:Synaptic Transmission
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011950:Receptors, Cholinergic; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein