Abstract
Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.
Highlights
Neuronal loss constitutes an irreversible end point of several neurodegenerative conditions triggered by diverse stimuli
We used an in vivo approach combining invertebrate (C. elegans) and vertebrate model systems to identify a novel and unexpected player in the mechanisms of axonal degeneration
We demonstrate that both neuronal somas and axons degenerate through a step dependent on oxidative stress that can be efficiently delayed by genetic downregulation of a pathway controlling oxidative stress resistance
Summary
Neuronal loss constitutes an irreversible end point of several neurodegenerative conditions triggered by diverse stimuli. Early neuronal dysfunction is associated with degeneration of neuronal processes, including axons and dendrites, causing a progressive loss of neuronal function [1,2]. Much of our current knowledge regarding the mechanisms of axonal degeneration originates from studies in the Wlds mice, which show delayed axonal degeneration caused by mechanical injuries, hypoxia and other toxic stimuli [5]. Slowing down axonal degeneration by Wlds expression in mouse models of neurodegenerative conditions delays the disease progression and severity [10,11,12], pointing out to a crucial role of axonal degeneration in diseases of varied nature
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