Inhibiting acute, axonal DLK palmitoylation is neuroprotective and avoids deleterious effects of cell-wide DLK inhibition.

ABSTRACT: Inhibiting dual leucine-zipper kinase (DLK) could potentially ameliorate diverse neuropathological conditions, but a direct inhibitor of DLK's kinase domain caused unintended side effects in human patients, indicative of neuronal cytoskeletal disruption. We sought a more precise intervention and show here that axon-to-soma pro-degenerative signaling requires acute, axonal palmitoylation of DLK. To identify potential modulators of this modification, we screened >28,000 compounds using a high-content imaging readout of DLK's palmitoylation-dependent subcellular localization. Several hits alter DLK localization in non-neuronal cells, reduce DLK retrograde signaling and protect cultured dorsal root ganglion neurons from neurodegeneration. Mechanistically, the two most neuroprotective compounds

SUBMITTER: Zhang X 

PROVIDER: S-EPMC11968826 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature