The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy.

Hong Liu,Armin Yazdani,Rashmi Kothary,Ariane Beauvais,Lyndsay M Murray,Gilbert Bernier

doi:10.1371/journal.pone.0101225

Abstract

Spinal muscular atrophy is an autosomal recessive neuromuscular disease characterized by the progressive loss of alpha motor neurons in the spinal cord. Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. It is currently unclear whether TSA specifically targets the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-SMN mediated pathway. TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/- mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Of interest, TSA treatment did not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. In addition, no change in the level of Smn transcripts or protein in the brain or spinal cord of TSA-treated SMA model mice was observed. Furthermore, TSA did not increase Smn protein levels in the hind limb muscle, heart, or liver of Smn2B/- mice. We therefore conclude that TSA likely exerts its effects independent of the endogenous mouse Smn gene. As such, identification of the pathways regulated by TSA in the Smn2B/- mice could lead to the development of novel therapeutics for treating SMA.

Highlights

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the progressive loss of alpha motor neurons in the anterior horn region of the spinal cord
We tested the efficacy of Trichostatin A (TSA) in the Smn2B/- mouse model, which does not carry the human SMN2 transgene
We have shown that TSA administration have beneficial effects in the Smn2B/- mouse model

Summary

Introduction

Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the progressive loss of alpha motor neurons in the anterior horn region of the spinal cord. SMA is caused by homozygous deletions or rare missense mutations in the survival motor neuron 1 (SMN1) gene [1]. SMA is caused by deletions in SMN1, all patients retain at least one copy of the near identical SMN2 gene. Rodent species only carry a single survival of motor neuron gene (Smn) and its inactivation leads to early embryonic lethality [6]. A number of strategies have been employed to generate viable mouse models of SMA. The Smn-/-;SMN2;SMND7 mouse model of SMA ( referred to as the delta 7 mouse model) contains 2 copies of the human SMN2 onto a Smn-/background and carries 2 copies of the delta 7 SMN cDNA. An alternative approach has been to introduce a three-nucleotide substitution in the exon 7 splicing enhancer of the murine Smn gene, generating a model known as the Smn2B/- mouse model [9], [10]

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Conclusion