Journal Article

Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy

Sumner, Charlotte J., Cizman, Ziga, Fischbeck, Kenneth H., Pellizzoni, Livio, Di Prospero, Nicholas A., Taye, Addis A., Avila, Amy M., Knight, Melanie A., Gabanella, Francesca, Burnett, Barrington G., Hartenstein, Parvana

2007

Overview

The inherited motor neuron disease spinal muscular atrophy (SMA) is caused by mutation of the telomeric survival motor neuron 1 (SMN1) gene with retention of the centromeric SMN2 gene. We sought to establish whether the potent and specific hydroxamic acid class of histone deacetylase (HDAC) inhibitors activates SMN2 gene expression in vivo and modulates the SMA disease phenotype when delivered after disease onset. Single intraperitoneal doses of 10 mg/kg trichostatin A (TSA) in nontransgenic and SMA model mice resulted in increased levels of acetylated H3 and H4 histones and modest increases in SMN gene expression. Repeated daily doses of TSA caused increases in both SMN2-derived transcript and SMN protein levels in neural tissues and muscle, which were associated with an improvement in small nuclear ribonucleoprotein (snRNP) assembly. When TSA was delivered daily beginning on P5, after the onset of weight loss and motor deficit, there was improved survival, attenuated weight loss, and enhanced motor behavior. Pathological analysis showed increased myofiber size and number and increased anterior horn cell size. These results indicate that the hydroxamic acid class of HDAC inhibitors activates SMN2 gene expression in vivo and has an ameliorating effect on the SMA disease phenotype when administered after disease onset.

• Publisher: American Society for Clinical Investigation
• Subject: Acids / Animals / Atrophy / Biomedical research / Cells, Cultured / Cyclic AMP Response Element-Binding Protein - analysis / Cyclic AMP Response Element-Binding Protein - genetics / Cyclic AMP Response Element-Binding Protein - metabolism / Disease Models, Animal / Drug dosages / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Fibroblasts / Gene expression / Gene Expression - drug effects / Genotype & phenotype / Histone Deacetylase Inhibitors / Humans / Hydroxamic Acids - pharmacology / Hydroxamic Acids - therapeutic use / Mice / Motor neurone disease / Muscular Atrophy, Spinal - drug therapy / Nerve Tissue Proteins - analysis / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Patients / Proteins / Ribonucleoproteins, Small Nuclear / RNA-Binding Proteins - analysis / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Rodents as laboratory animals / SMN Complex Proteins / Spinal muscular atrophy / Survival of Motor Neuron 1 Protein / Survival of Motor Neuron 2 Protein