Palmitoylation enables MAPK-dependent proteostasis of axon survival factors

Significance Neurons extend long structures called axons that are highly susceptible to damage and undergo degeneration in many neurological disorders. One strategy for treating these diseases is by elevating the abundance of axon survival factors that suppress axon death. Herein, we describe a protein homeostasis network that regulates axon degeneration by tuning the local levels of axon survival factors. In particular, we find that small-molecule inhibitors targeting a MAPK stress pathway protect axons from pathological degeneration by elevating the local abundance of axon survival factors NMNAT2 and SCG10. Furthermore, we discover that intracellular location imparts sensitivity to distinct protein homeostasis networks. Inactivating multiple nodes in this protein homeostasis network confers maximal therapeutic potential in diseases of axon degeneration.