Reactive oxygen species (ROS) are highly toxic compounds produced in different metabolic processes. Normally, cells are capable of defending against such agents by the action of enzymes that degrade. However, increased ROS levels above the acceptable physiological limits leads to oxidative stress that may alter normal cellular functions and trigger cell death. In fact, oxidative stress in nerve cells is clearly implicated in the progression of various neurodegenerative diseases like Alzheimer’s and amyotrophic lateral sclerosis. In this sense, the study of the mechanisms that control oxidative cell death is an important part of current research of these diseases.

Neuronal death by oxidative stress occurs through the action of the transcription factor FOXO3a. Under normal conditions, FOXO3a is phosphorylated and inactive by the action of AKT, a kinase whose activity is enhanced by the action of different trophic factors among which is factored in insulin-like growth I (IGF-I). The research group in neuroendocrinology Cajal Institute led by Prof. Ignacio Torres-German studies for years the role of IGF-I and neuronal survival factor.

In this recent work have shown that activation of FOXO3a by oxidative stress and subsequent neuronal death occurs through two mechanisms. On the one hand, reduces AKT inhibition through blockade of IGF-I signal. In parallel, activation of JNK2 occurs, another kinase that acts on FOXO3a, in this case activating. Both regulatory mechanisms occur independently in response to excess ROS and both are needed to produce cell death. The identification of molecules involved in these mechanisms provide new targets for drug design that may allow to more effectively combat neurodegenerative diseases associated with oxidative stress.