Visit our Expo - Redox and Inflammation signaling 2012

Inhibition of histone deacetylase activity as a therapeutic tool in amyotrophic lateral
sclerosis.
Caroline ROUAUX, Irina PANTELEEVA, Frédérique RENE, Jose-Luis GONZALEZ
de AGUILAR, Anne-Laurence BOUTILLIER & Jean-Philippe LOEFFLER
Laboratoire de Signalisation Moléculaire et Neurodégénérescence – INSERM U692 -
Faculté de Médecine - 11, rue Humann - 67085 Strasbourg Cedex FRANCE. Tel.: (+33)
390 24 30 88 Fax: (+33) 390 24 30 65.
Motoneuronal death in the spinal cord is a characteristic of Amyotrophic Lateral Sclerosis
(ALS). Our recent data showed a decrease in histone acetylation levels, as well as in protein
levels of the CREB-Binding Protein (CBP), a specific Histone Acetyl Transferase (HAT), in
motoneurons from the lumbar spinal cord of an in vivo mouse model of ALS (SOD1 G86R
mice) when compared to those of wild type animals. The aim of this study was to investigate
whether preventing the loss of acetylation by blocking histone deacetylases with specific
inhibitors (HDACi) could have an impact on motoneuronal death. Therefore, SOD1 G86R
mice were treated with the HDACi Sodium Valproate (VPA) at 250mg/kg/j, IP. VPA
treatment induced a delay in the onset of the symptoms, an increase in motor performances
and allowed to significantly reduce motoneuronal death. To study the mechanism of action of
this HDACi, we used a cellular model of motoneurons (the NSC34 neuroblastoma X Spinal
cord cell line) in which oxidative-stress induced-death was mimicked with a pulse of
hydrogen peroxide (H 2O 2). H 2O 2-induced motorneuronal death was accompanied by histone
deacetylation and CBP loss. Moreover, this loss resulted from a direct cbp gene repression.
Several HDACi (Trichostatin A: TSA, Sodium Valproate: VPA and Sodium Butyrate: NaBu)
were tested. We found that a long-term treatment with each compound had a significant
protective effect on H 2O 2-induced motoneuronal death, reversing histone acetylation decrease
and promoting cbp gene expression. Consequently, despite the effects of HDACi on the
neuromuscular junction remain to be elucidated, we believe that their beneficial effects in the
ALS model may result from a protection against motoneurons degeneration.
Rouaux et al., 2003, EMBO 22(24):6537-49
Rouaux et al., 2004, Biochem Pharmacol. 2004, 68(6):1157-64.
Supported by AFM and ARS.
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