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1.
PLoS One ; 8(9): e75866, 2013.
Article in English | MEDLINE | ID: mdl-24086650

ABSTRACT

In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA), lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN). Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre) as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+) ) as a driver on the same mice, and another report that used Hb9(Cre) as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+) mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ) denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+) SMA mice relative to ChAT(Cre+) SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre) . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.


Subject(s)
Motor Neurons/physiology , Muscular Atrophy, Spinal/physiopathology , Muscular Atrophy, Spinal/therapy , Phenotype , SMN Complex Proteins/metabolism , Synapses/physiology , Animals , DNA Primers/genetics , Genotype , Mice , Motor Endplate/metabolism , Motor Endplate/physiology , Real-Time Polymerase Chain Reaction , Survival Analysis
2.
J Neurosci ; 32(25): 8703-15, 2012 Jun 20.
Article in English | MEDLINE | ID: mdl-22723710

ABSTRACT

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.


Subject(s)
Motor Neurons/metabolism , Motor Neurons/pathology , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/pathology , SMN Complex Proteins/metabolism , Synapses/pathology , Animals , Blotting, Western , DNA/genetics , Electrophysiological Phenomena , Genotype , Immunohistochemistry , Mice , Microscopy, Electron , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/innervation , Muscle, Skeletal/pathology , Muscular Atrophy, Spinal/genetics , Neural Pathways/metabolism , Neural Pathways/pathology , Neuromuscular Junction/metabolism , Neuromuscular Junction/pathology , Patch-Clamp Techniques , Phenotype , Polymerase Chain Reaction , SMN Complex Proteins/biosynthesis , SMN Complex Proteins/genetics , Survival of Motor Neuron 1 Protein , Survival of Motor Neuron 2 Protein
3.
Hum Mol Genet ; 20(9): 1844-53, 2011 May 01.
Article in English | MEDLINE | ID: mdl-21325354

ABSTRACT

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by the mutation of the survival motor neuron 1 (SMN1) gene and deficiency of the SMN protein. Severe SMA mice have abnormal motor function and small, immature myofibers early in development suggesting that SMN protein deficiency results in retarded muscle growth. Insulin-like growth factor 1 (IGF-1) stimulates myoblast proliferation, induces myogenic differentiation and generates myocyte hypertrophy in vitro and in vivo. We hypothesized that increased expression of IGF-1 specifically in skeletal muscle would attenuate disease features of SMAΔ7 mice. SMAΔ7 mice overexpressing a local isoform of IGF-1 (mIGF-1) in muscle showed enlarged myofibers and a 40% increase in median survival compared with mIGF-1-negative SMA littermates (median survival = 14 versus 10 days, respectively, log-rank P = 0.025). Surprisingly, this was not associated with a significant improvement in motor behavior. Treatment of both mIGF-1(NEG) and mIGF-1(POS) SMA mice with the histone deacetylase inhibitor, trichostatin A (TSA), resulted in a further extension of survival and improved motor behavior, but the combination of mIGF-1 and TSA treatment was not synergistic. These results show that increased mIGF-1 expression restricted to muscle can modulate the phenotype of SMA mice indicating that therapeutics targeted to muscle alone should not be discounted as potential disease-modifying therapies in SMA. IGF-1 may warrant further investigation in mild SMA animal models and perhaps SMA patients.


Subject(s)
Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy, Spinal/metabolism , Up-Regulation , Animals , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Knockout , Motor Activity , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/physiopathology , SMN Complex Proteins/genetics , SMN Complex Proteins/metabolism
4.
Nat Genet ; 42(2): 170-4, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20037586

ABSTRACT

Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory protein-protein interactions.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Mutation/genetics , TRPV Cation Channels/genetics , Adolescent , Adult , Aged , Amino Acid Sequence , Amino Acid Substitution/genetics , Ankyrin Repeat , Base Sequence , Cell Membrane/metabolism , Charcot-Marie-Tooth Disease/physiopathology , DNA Mutational Analysis , Female , Humans , Ion Channel Gating , Male , Middle Aged , Models, Molecular , Molecular Sequence Data , Mutant Proteins/metabolism , Neurotoxins , Pedigree , Phenotype , TRPV Cation Channels/chemistry , Young Adult
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