Although the activities of many signaling pathways are dysregulated during the progression of neurodegenerative and muscle degeneration disorders, the precise sequence of cellular events leading to degeneration has not been fully elucidated. Two kinases of particular interest, the growth-promoting Tor kinase and the energy sensor AMPK, appear to show reciprocal changes in activity during degeneration, with increased Tor activity and decreased AMPK activity reported. These changes in activity have been predicted to cause degeneration by attenuating autophagy, leading to the accumulation of unfolded protein aggregates and dysfunctional mitochondria, the consequent increased production of reactive oxygen species (ROS), and ultimately oxidative damage. Here we propose that this increased ROS production not only causes oxidative damage but also ultimately induces an oxidative stress response that reactivates the redox-sensitive AMPK and activates the redox-sensitive stress kinase JNK. Activation of these kinases reactivates autophagy. Because at this late stage, cells have become filled with dysfunctional mitochondria and protein aggregates, which are autophagy targets, this autophagy reactivation induces degeneration. The mechanism proposed here emphasizes that the process of degeneration is dynamic, that dysregulated signaling pathways change over time and can transition from deleterious to beneficial and vice versa as degeneration progresses.
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We are grateful to Drs. Saurabh Srivastav and Kevin van der Graaf for comments on the manuscript. This work was funded by NIH grant R01 NS102676 awarded to MS and JAM.
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The authors declare that they have no conflict of interest.
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Stern, M., McNew, J.A. A transition to degeneration triggered by oxidative stress in degenerative disorders. Mol Psychiatry 26, 736–746 (2021). https://doi.org/10.1038/s41380-020-00943-9
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