Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice
Article first published online: 29 MAR 2005
Journal of Neurochemistry
Volume 93, Issue 5, pages 1087–1098, June 2005
How to Cite
Ryu, H., Smith, K., Camelo, S. I., Carreras, I., Lee, J., Iglesias, A. H., Dangond, F., Cormier, K. A., Cudkowicz, M. E., H. Brown, R. and Ferrante, R. J. (2005), Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. Journal of Neurochemistry, 93: 1087–1098. doi: 10.1111/j.1471-4159.2005.03077.x
- Issue published online: 26 APR 2005
- Article first published online: 29 MAR 2005
- Received November 30, 2004; revised manuscript received January 4, 2005; accepted January 5, 2005.
- amyotrophic lateral sclerosis;
- histone deacetylase inhibition;
- programmed cell death;
- transgenic G93A mice
Multiple molecular defects trigger cell death in amyotrophic lateral sclerosis (ALS). Among these, altered transcriptional activity may perturb many cellular functions, leading to a cascade of secondary pathological effects. We showed that pharmacological treatment, using the histone deacetylase inhibitor sodium phenylbutyrate, significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice. Phenylbutyrate administration ameliorated histone hypoacetylation observed in G93A mice and induced expression of nuclear factor-κB (NF-κB) p50, the phosphorylated inhibitory subunit of NF-κB (pIκB) and beta cell lymphoma 2 (bcl-2), but reduced cytochrome c and caspase expression. Curcumin, an NF-κB inhibitor, and mutation of the NF-κB responsive element in the bcl-2 promoter, blocked butyrate-induced bcl-2 promoter activity. We provide evidence that the pharmacological induction of NF-κB-dependent transcription and bcl-2 gene expression is neuroprotective in ALS mice by inhibiting programmed cell death. Phenylbutyrate acts to phosphorylate IκB, translocating NF-κB p50 to the nucleus, or to directly acetylate NF-κB p50. NF-κB p50 transactivates bcl-2 gene expression. Up-regulated bcl-2 blocks cytochrome c release and subsequent caspase activation, slowing motor neuron death. These transcriptional and post-translational pathways ultimately promote motor neuron survival and ameliorate disease progression in ALS mice. Phenylbutyrate may therefore provide a novel therapeutic approach for the treatment of patients with ALS.