Role of oxidative stress in neurological disorders
Oxidative stress and excitotoxicity have been identified as the main pathological processes involved in ischaemic stroke, as well as in multiple neurodegenerative disorders. Over-activation of glutamate receptors in neurons leads to a massive calcium uptake which, in turn, generates reactive oxygen species (ROS). Abnormal levels of ROS cannot be successfully compensated for by the cell, inducing oxidative stress with detrimental effects for cell physiology. To further understand the pathophysiology of neural injury caused by excitotoxicity/oxidative stress, the SIM-ON project looked at the activation of cytoprotective and pro-apoptotic gene expression in neurons and astrocytes. The main aim was to identify the key stages in the cell fate decision between tolerance and apoptosis in response to oxidative stress. Scientists discovered that over-excitation of neurons resulted in the activation of the protein kinase AMPK, which is instrumental for cell survival. However, it was found that prolonged activation of AMPK stimulated apoptosis by inducing the expression of the pro-apoptotic protein Bim. Mathematical modelling revealed that this mechanism correlates with a preserved pattern of interactions known as a coherent feed-forward loop. Furthermore, a cytoprotective mechanism which prevents neuronal apoptosis during oxidative stress was discovered. It involved activation of the heat shock protein 27 (Hsp27) that regulated Bim to prevent neuronal apoptosis. SIM-ON results pointed towards key cellular mechanisms involved in either neuronal protection or neuronal death during oxidative stress or excitotoxic injuries. Modulation of these pathways has the potential to lead to novel therapeutic strategies with reduced neuronal death and brain function deterioration.
