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

Xiaotian Zhang, Heykyeong Jeong, Jingwen Niu, Sabrina M. Holland, Brittany N. Rotanz, John Gordon, Margret B. Einarson, Wayne E. Childers and Gareth M. Thomas ()
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Xiaotian Zhang: Lewis Katz School of Medicine at Temple University
Heykyeong Jeong: Lewis Katz School of Medicine at Temple University
Jingwen Niu: Lewis Katz School of Medicine at Temple University
Sabrina M. Holland: Lewis Katz School of Medicine at Temple University
Brittany N. Rotanz: Lewis Katz School of Medicine at Temple University
John Gordon: Temple University
Margret B. Einarson: Fox Chase Cancer Center
Wayne E. Childers: Temple University
Gareth M. Thomas: Lewis Katz School of Medicine at Temple University

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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 selectively prevent DLK’s stimulus-dependent palmitoylation and subsequent recruitment to axonal vesicles, but do not affect palmitoylation of other axonal proteins assessed and avoid the cytoskeletal disruption associated with direct DLK inhibition. Our hit compounds also reduce pro-degenerative retrograde signaling in vivo, revealing a previously unrecognized neuroprotective strategy.

Date: 2025
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DOI: 10.1038/s41467-025-58036-6

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