ROS regulate developmental and pathological denervation in vivo

The neuromuscular junction (NMJ) defines the functional interface between nerve and muscle. Reactive oxygen species (ROS) are linked to pathological denervation in multiple neurodegenerative diseases, but whether and how ROS cause denervation is unclear. Our hypothesis is that ROS reiteratively repeat the signaling pathways of developmental denervation to cause pathological denervation in multiple diseases. The stage 37-38 Xenopus Laevis model allows us to “hi-jack” the systems of functional denervation and track cellular changes in vivo. To address our hypothesis, we used SPARC to induce developmental denervation. SPARC induced both denervation and increased ROS levels. MnTE-2-PyP5+ and MnTnBuOE -2-PyP5+, two antioxidants, block ROS to abolish SPARC induced denervation. Next, we used α-Latrotoxin, α-Bungarotoxin and Mito-Paraquat to mimic pathological nerve, muscle and environmental toxin induced denervation, respectively. Analogous to SPARC, each pathological denervation model increases ROS. Strikingly, MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+ block ROS to abolish pathological denervation in each of the three models. We conclude that ROS are a shared biochemical feature of pathological denervation, recapitulating an endogenous redox regulated developmental denervation pathway.