Abstract
Reactive oxygen species (ROS) are generated during physiological bouts of synaptic activity and as a consequence of pathological conditions in the central nervous system. How neurons respond to and distinguish between ROS in these different contexts is currently unknown. In Drosophila mutants with enhanced JNK activity, lower levels of ROS are observed and these animals are resistant to both changes in ROS and changes in synapse morphology induced by oxidative stress. In wild type flies, disrupting JNK-AP-1 signalling perturbs redox homeostasis suggesting JNK activity positively regulates neuronal antioxidant defense. We validated this hypothesis in mammalian neurons, finding that JNK activity regulates the expression of the antioxidant gene Srxn-1, in a c-Jun dependent manner. We describe a conserved ‘adaptive’ role for neuronal JNK in the maintenance of redox homeostasis that is relevant to several neurodegenerative diseases.
Highlights
Active neurons generate reactive oxygen species (ROS) predominantly as a by-product of mitochondrial respiration
We have previously found that food containing 5 mM and 10 mM DEM which depletes glutathione levels, is sufficient to induce an overgrowth at the larval neuromuscular junction (NMJ) [5], with 10 mM concentrations being detrimental to survival (Fig. S1, 6% of flies pupate)
We show that Drosophila mutants that have enhanced JNK activity have low levels of ROS and are resistant to chemically induced oxidative stress
Summary
Active neurons generate reactive oxygen species (ROS) predominantly as a by-product of mitochondrial respiration. ROS levels are neutralized by constitutive and adaptive reductive mechanisms operating in neurons and glia, including the glutathione system [1,2,3]. In this manner, the amplitude and temporal dynamics of the ROS signal are controlled, damage is limited and transient ROS signals can be interpreted in part to support the growth and plasticity of neurons [4,5]. In many neurodegenerative disorders the reductive capacity of neurons is overwhelmed, contributing to disease progression [4,8] These damaging levels of ROS, termed oxidative stress, overwhelm neuronal antioxidant defenses. Similar changes in synaptic structure can be induced directly by application of oxidants such as paraquat [12] or diethylmaleate (DEM) [5], or through genetic activation of JNK via manipulation of the JNKK hemipterous [15] (hep) or the JNKKK Wallenda [11] (wnd), upstream activators of JNK
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