JNK Signalling Mediates Context-Dependent Responses to Reactive Oxygen Species in Neurons

Reactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and can also contribute to pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. During synaptic activity, a JNK-independent c-Fos/c-Jun AP-1 heterodimer activates transcription of the SRXN1 antioxidant response. Under conditions of oxidative stress, an adaptive JNK-dependent c-Jun/c-Jun AP-1 homodimer is selectively activated by accumulation of ROS to drive SRXN1 expression. This fundamental signaling pathway is conserved in the Drosophila nervous system. In Drosophila highwire mutants, which have constitutively active JNK, basal ROS levels are lower than in wild-type flies, but can be reinstated by pan-neuronal JNK inhibition. We have identified a conserved adaptive role for neuronal JNK signaling in directing the composition of AP-1 dimers to mount an antioxidant response and maintain redox homeostasis during ROS accumulation that is relevant to several neurodegenerative diseases.