Survival motor neuron protein in motor neurons determines synaptic integrity in spinal muscular atrophy.
The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein and results in severe muscle weakness. In SMA mice, synaptic dysfunction of both neuromuscular junctions (NMJs) and central sensorimotor synapses precedes motor neuron cell death. To address whether this synaptic dysfunction is due to SMN deficiency in motor neurons, muscle, or both, we generated three lines of conditional SMA mice with tissue-specific increases in SMN expression. All three lines of mice showed increased survival, weights, and improved motor behavior. While increased SMN expression in motor neurons prevented synaptic dysfunction at the NMJ and restored motor neuron somal synapses, increased SMN expression in muscle did not affect synaptic function although it did improve myofiber size. Together these data indicate that both peripheral and central synaptic integrity are dependent on motor neurons in SMA, but SMN may have variable roles in the maintenance of these different synapses. At the NMJ, it functions at the presynaptic terminal in a cell-autonomous fashion, but may be necessary for retrograde trophic signaling to presynaptic inputs onto motor neurons. Importantly, SMN also appears to function in muscle growth and/or maintenance independent of motor neurons. Our data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power.
Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Tara L
TL
Martinez
Lingling
L
Kong
Xueyong
X
Wang
Melissa A
MA
Osborne
Melissa E
ME
Crowder
James P
JP
Van Meerbeke
Xixi
X
Xu
Crystal
C
Davis
Joe
J
Wooley
David J
DJ
Goldhamer
Cathleen M
CM
Lutz
Mark M
MM
Rich
Charlotte J
CJ
Sumner
D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D055724:Electrophysiological Phenomena; D005838:Genotype; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D016133:Polymerase Chain Reaction; D055532:SMN Complex Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013569:Synapses / Q000473:pathology*
D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D004247:DNA