Neuronal Death
Molecular details of GSK-3 action in neuronal death
Our quest to unravel the signaling molecules regulating death in neurons has included a study of lithium. Lithium has been used as an effective mood stabilising drug for treatment of manic episodes and depression for 50 years. More recently, lithium has been recognised to protect neurons from death induced by a wide array of neurotoxic insults. However, the molecular basis for the prophylactic effects of lithium have remained obscure. Lithium also profoundly effects morphogenesis and cell fate determination in developing organisms, effects attributed to direct inhibition of glycogen synthase kinase-3 (GSK-3). Lithium is not an ideal drug being both teratogenic and toxic at doses close to those required for therapeutic benefit, it is nevertheless widely used and has clinically relevant neuroprotective effects. We have shown that lithium blocks the canonical c-Jun apoptotic pathway in neurons. This identifies a neuroprotective mechanism for lithium action in the brain and reveals a novel action for GSK-3 in facilitation of the c-Jun stress response during neuronal death.
Model depicting the cooperative action of JNK and GSK-3 in regulating stress induced neuronal death (Hongisto et al., Mol. Cell. Biol., 2003).