title: Increasing expression and decreasing degradation of SMN ameliorate the spinal muscular atrophy phenotype in mice.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by reduced levels of the survival motor neuron (SMN) protein. Here we show that the proteasome inhibitor, bortezomib, increases SMN in cultured cells and in peripheral tissues of SMA model mice. Bortezomib-treated animals had improved motor function, which was associated with reduced spinal cord and muscle pathology and improved neuromuscular junction size, but no change in survival. Combining bortezomib with the histone deacetylase inhibitor trichostatin A (TSA) resulted in a synergistic increase in SMN protein levels in mouse tissue and extended survival of SMA mice more than TSA alone. Our results demonstrate that a combined regimen of drugs that decrease SMN protein degradation and increase SMN gene transcription synergistically increases SMN levels and improves the lifespan of SMA model mice. Moreover, this study indicates that while increasing SMN levels in the central nervous system may help extend survival, peripheral tissues can also be targeted to improve the SMA disease phenotype.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors.forename: Deborah Y
authors.initials: DY
authors.lastname: Kwon
authors.forename: William W
authors.initials: WW
authors.lastname: Motley
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D059748:Proteolysis; D013534:Survival; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D055533:Survival of Motor Neuron 1 Protein