Ultrastructural changes in diaphragm neuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy and their prevention by bifunctional U7 snRNA correcting SMN2 splicing

Abstract In Spinal Muscular Atrophy (SMA), the SMN1 gene is deleted or inactivated. Because of a splicing problem, the second copy gene, SMN2 , generates insufficient amounts of functional SMN protein, leading to the death of spinal cord motoneurons. For a “severe” mouse SMA model ( Smn −/−, hSMN2 +...

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Bibliographic Details
Published in:Neuromuscular disorders : NMD 2010-11, Vol.20 (11), p.744-752
Main Authors: Voigt, Tilman, Meyer, Kathrin, Baum, Oliver, Schümperli, Daniel
Format: Article
Language:English
Subjects:
Animal models
Animals
Diaphragm
Diaphragm - pathology
Diaphragm - ultrastructure
Disease Models, Animal
Fibroblasts
Mice
Mice, Transgenic
Microscopy, Electron, Transmission
Mitochondria
Mitochondria - diagnostic imaging
Mitochondria - pathology
Motor neurons
Motor Neurons - pathology
Motor Neurons - ultrastructure
Mouse models
Muscle, Skeletal - diagnostic imaging
Muscle, Skeletal - pathology
Muscles
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - pathology
Neurology
Neuromuscular Junction - genetics
Neuromuscular Junction - pathology
Neuromuscular Junction - ultrastructure
Neuromuscular junctions
neuromuscular system
Perisynaptic Schwann cells
Reverse Transcriptase Polymerase Chain Reaction
Schwann cells
SMN protein
snRNA
soleus muscle
Spinal cord
Spinal Muscular Atrophy
Splicing
Survival of Motor Neuron 2 Protein - genetics
Ultrasonography
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Summary:Abstract In Spinal Muscular Atrophy (SMA), the SMN1 gene is deleted or inactivated. Because of a splicing problem, the second copy gene, SMN2 , generates insufficient amounts of functional SMN protein, leading to the death of spinal cord motoneurons. For a “severe” mouse SMA model ( Smn −/−, hSMN2 +/+; with affected pups dying at 5–7 days), which most closely mimicks the genetic set-up in human SMA patients, we characterise SMA-related ultrastructural changes in neuromuscular junctions (NMJs) of two striated muscles with discrete functions. In the diaphragm, but not the soleus muscle of 4-days old SMA mice, mitochondria on both sides of the NMJs degenerate, and perisynaptic Schwann cells as well as endoneurial fibroblasts show striking changes in morphology. Importantly, NMJs of SMA mice in which a modified U7 snRNA corrects SMN2 splicing and delays or prevents SMA symptoms are normal. This ultrastructural study reveals novel features of NMJ alterations – in particular the involvement of perisynaptic Schwann cells – that may be relevant for human SMA pathogenesis.
ISSN:0960-8966
1873-2364
DOI:10.1016/j.nmd.2010.06.010