Sodium Valproate Exerts Neuroprotective EffectsIn Vivothrough CREB-Binding Protein-Dependent Mechanisms But Does Not Improve Survival in an Amyotrophic Lateral Sclerosis Mouse Model

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by motoneuron (MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 (mSOD1), we demonstrated previously that CREB (cAMP response element-binding protein)-binding protein (CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor (HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stress in vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R mice in vivo, the HDACi sodium valproate (VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved (Ͻ5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Sodium phenylbutyrate combined with an antioxidant [124] or riluzole [125] showed a beneficial effect. However, in the G86R mouse model, valproate restored histone acetylation in the spinal cord and CBP levels in motor neurons, but failed to improve mice survival, as a major detrimental effect on the neuromuscular junction was observed [126].…”

“…However, an increase of p53 acetylation on K382, a known substrate for p300/CBP and HDAC SIRT1, induced apoptotic functions [138]. Thus, the CBP loss [76,126] and SIRT1 overexpression [139] observed in motor neurons might induce a neuroprotective effect.…”

“…In particular, the effect of HAT activation in the neuromuscular junction, which is tightly regulated through chromatin acetylation [141,142], has not been documented; however, studies have shown the deleterious effect of valproate [126].…”

“…A therapeutic strategy based on CBP/p300 reactivation could be useful, even in the adult, for re-establishing at least some cognitive functions [198,212], particularly for ALS, in which motor neurons present lower quantities of CBP owing to degradation [76]. In addition, HDACi are poorly efficient in this context, as these molecules were deleterious for the neuromuscular junction, despite a significant improvement of motor neuron survival [126]. A HAT activator could also be relevant for its use in AD and related diseases, as this molecule could improve both neuronal survival, neurogenesis, and memory-related alterations (see below).…”

Sclérose latérale amyotrophique, jonction neuromusculaire et déficit énergétique

“…De plus, trois études récentes ont montré que la protection du corps cellulaire du motoneurone, et donc la préserva-tion du nombre de corps cellulaires de motoneurones dans la moelle épinière, ne permettaient pas de guérir la souris SOD1m [8][9][10] : l'ablation de bax, un gène clé de l'apoptose dans le motoneurone, abolit complète-ment l'apoptose du motoneurone mais ne retarde que modestement la mort de l'animal et la dénervation musculaire [9]. De même, le valproate de sodium, qui inhibe le remodelage de la chromatine lors de l'apoptose du motoneurone, ou un inhibiteur de P38 MAPK, une protéine kinase intervenant dans les étapes initiales de l'apoptose, sont capables de protéger le corps cellulaire du motoneurone, mais ne retardent pas ou peu la dénervation musculaire et la mort de l'animal [8,10]. Comment interpréter ces résultats ?…”