Investigate the Role of ROS and RNS in Axon Degeneration

Following injury, sensory neuron terminals rapidly degenerate before initiating regeneration. While reactive oxygen species (ROS) are known to promote axon regeneration through epidermal mechanisms, their role in axon degeneration remains unclear. A hallmark of neurodegenerative diseases is the formation of mitochondrial ROS (mitoROS), but whether mitoROS contribute to injury-induced axon degeneration was unknown.

Here, I demonstrate that mitochondrial superoxide in cutaneous sensory neurons drives axon degeneration following fin amputation. Further analysis showed that reactive nitrogen species (RNS), specifically peroxynitrite, are formed by superoxide and contribute to axonal destruction. I identified putative nitration and nitrosylation sites at conserved residues in NMNAT, a key regulator of SARM1-driven axon degeneration. Modulation of ROS/RNS with the ROS scavenger NADPH significantly reduced amputation-induced sensory axon degeneration while enhancing the regeneration of cutaneous axons. Furthermore, NADPH co-administration mitigated axon degeneration under pathological conditions induced by paclitaxel, suggesting that oxidative stress-induced axon degeneration extends beyond injury models and may underlie broader neurotoxic mechanisms.

To further investigate the role of ROS in paclitaxel-induced axon degeneration, I examined the expression and function of the ROS-producing enzyme Nox1 in the presence and absence of paclitaxel. Paclitaxel treatment induced a nuclear translocation of Nox1 in epidermal keratinocytes, leading to increased nuclear ROS formation and upregulation of mmp13 transcription. Sensory axon degeneration was prevented in cyba-/- mutants, which impair Nox1 activity, confirming a role for Nox-induced ROS in paclitaxel neurotoxicity. These findings suggest that ROS contribute to axon degeneration through distinct mechanisms: extrinsically via keratinocyte-mediated Nox1 signaling in paclitaxel-induced pathology and intrinsically through mitochondrial superoxide in acute injury-induced degeneration.