Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the motor system and has a fatal outcome. For a long time it has been assumed that motor-neuron death is connected to the onset of the disease and that protecting these neurons could reduce mortality. Loeffler and colleagues have now demonstrated in a transgenic mouse model for ALS that although sodium valproate (VPA) has a neuroprotective effect on motor neurons, disease onset and progression are unaltered.

Oxidative stress has been suggested to cause motor-neuron death in ALS. Mutations in superoxide dismutase-1 (SOD1), a protein involved in the protection of cells against oxidative stress, are one of the known genetic causes for ALS. Transgenic mice carrying mutations in Sod1, such as G86R mice, are an established mouse model for ALS. In G86R mice, the authors previously showed that cyclic AMP response element-binding protein (CREB) binding protein (CBP), a transcriptional coactivator with histone acetyltransferase (HAT) activity, is absent specifically from motor neurons. They therefore investigated whether VPA, an inhibitor of histone deacetylases (HDACs), could counterbalance the loss of HAT activity and prevent motor-neuron death and disease progression.

Using a wild-type motor neuron cell culture model, the authors showed that oxidative stress induced by hydrogen peroxide treatment reduced histone H3 acetylation levels and downregulated levels of CBP, which caused cell death. They found that oxidative stress led to the transcriptional repression of the cbp gene and that treatment with different HDAC inhibitors, including VPA, allowed the maintenance of CBP levels and exerted a neuroprotective effect.

VPA, which is an antiepileptic drug that is also used to treat bipolar disorders, can easily cross the blood–brain barrier. The authors investigated whether the neuroprotective effect of VPA was also beneficial in vivo in G86R mice. In the motor neurons of these mice, the histone acetylation levels were significantly decreased in comparison with those from wild-type mice. Chronic treatment of G86R mice with VPA prevented motor-neuron death in the initial stages of deterioration. Furthermore, motor neuron CBP levels, which were significantly reduced in G86R mice, were restored after VPA treatment. These results indicate that VPA re-establishes normal levels of histone acetylation by inhibiting HDACs and, as transcriptional activation is restored, that CBP is upregulated to normal levels. This also suggests that VPA's neuroprotective effect is connected to the CREB/CBP-dependent pathway, which is implemented in neuronal survival.

Although the effect of VPA on motor-neuron survival was striking, the effects of chronic VPA treatment on disease onset were only mild, and they did not alter neuromuscular junction denervation, the clinical progression of the disease or the lifespan of the mice.

This study presents the first evidence that inhibitors of HDAC can prevent neurodegeneration by modulating a CBP-dependent pathway in the pathological context of ALS. Uncoupling motor-neuron death from animal survival points towards the neuromuscular junction as the site for primary events of ALS onset. Future studies are required to further elucidate these events before ALS can be efficiently treated.