Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy
Amy M. Avila, … , Kenneth H. Fischbeck, Charlotte J. Sumner
Amy M. Avila, … , Kenneth H. Fischbeck, Charlotte J. Sumner
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):659-671. https://doi.org/10.1172/JCI29562.
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Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy

Abstract

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.

Authors

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

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Figure 7

TSA increases AHC size but not AHC number.

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TSA increases AHC size but not AHC number. SMA mice were treated with ve...
SMA mice were treated with vehicle (n = 3) or TSA (n = 3) and heterozygous littermates were treated with vehicle (n = 3) on days P5–P13. (A) Nissl-stained cross-sections of lumbar spinal cord showing 1 ventral horn. Scale bars: 10 μm. (B) Median ventral horn neuron number was reduced in SMA mice compared with heterozygous littermates (P < 0.0001) and was not changed by TSA treatment. Lines represent median values, boxes represents the twenty-fifth and seventy-fifth percentiles, whiskers represent values within 1.5 times the interquartile range, and dots represent outliers. (C) Median ventral horn neuron size was increased in heterozygous mice compared with SMA mice (P < 0.0001) and was increased by TSA treatment (P = 0.003). (D) ChAT mRNA levels were determined in spinal cord isolated from SMA mice treated daily with vehicle (n = 5) or TSA (n = 5) and heterozygous littermates treated with vehicle (n = 6) on days P5–P13.