title: The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy.
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.
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Yazdani
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Lyndsay M
authors.initials: LM
authors.lastname: Murray
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Ariane
authors.initials: A
authors.lastname: Beauvais
authors.affiliation: Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; D055540:Survival of Motor Neuron 2 Protein; C012589:trichostatin A