Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Abstract

AbstractAxons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence aged axons are more susceptible to damage or dysfunction. Understanding what causes axonal vulnerability is crucial for developing strategies to enhance overall resilience of neurons, and to prevent their deterioration during ageing or in age-related neurodegenerative diseases.Increasing levels of reactive oxygen species (ROS) causes oxidative stress, a hallmark of ageing and age-related diseases. Despite this association, a causal relationship between oxidative stress and neuronal ageing remains unclear, particularly how subcellular physiology is affected by ROS.By usingDrosophila-derived primary neuronal cultures and a recently developedin vivoneuronal model of ageing, which involves the visualisation ofDrosophilamedulla neurons, we investigated the interplay between oxidative stress, neuronal ageing and the microtubule cytoskeleton. We find that oxidative stress as a key driver of axonal and synaptic decay, including the appearance of axonal swellings, microtubule alterations in both axons and synapses and the morphological transformation of axonal terminals during ageing. We demonstrate that increased ROS sensitises the microtubule plus end binding factor, end-binding protein 1 (EB1), leading to microtubule defects, affecting neuronal integrity. Furthermore, manipulating EB1 proved to be a valuable therapeutic strategy to prevent ageing hallmarks observed in conditions of elevated ROS. In summary, we demonstrate a mechanistic pathway linking cellular oxidative stress, the microtubule cytoskeleton and axonal deterioration during ageing and provide evidence of the therapeutic potential of enhancing microtubule plus end physiology to improve the resilience of axons.