Rab11 suppresses neuronal stress signaling by localizing Dual leucine zipper kinase to axon terminals for protein turnover

Kim, Seungmi; Quagraine, Yaw; Singh, Monika; Kim, Jung Hwan

doi:10.1101/2023.04.18.537392

Cited by 2 publications

(1 citation statement)

References 89 publications

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“…Nonetheless, targeting other features of DLK, including specific interactions and/or post-translational modifications might still be of therapeutic benefit. In this study, we therefore focused on the regulation of DLK by palmitoylation, a modification that is critical for both axonal localization and signaling by DLK (8, 9, 17, 31). These conclusions were in part based on experiments in which loss of the protein acyltransferase (PAT) ZDHHC17, which plays an evolutionarily conserved role in controlling DLK palmitoylation and subsequent targeting to neuronal axons, was also found to block DLK-dependent retrograde signaling (9).…”

Section: Discussionmentioning

confidence: 99%

Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

Zhang,

Jeong,

Niu

et al. 2024

Preprint

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Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition of the kinase domain of DLK in human patients and conditional knockout of DLK in mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative of neuronal cytoskeletal disruption. Indeed, we found that a DLK kinase domain inhibitor acutely disrupted the axonal cytoskeleton and caused vesicle aggregation in cultured dorsal root ganglion (DRG) neurons, further cautioning against this therapeutic strategy. In seeking a more precise intervention, we found that retrograde (axon-to-soma) pro-degenerative signaling requires acute, axonal palmitoylation of DLK and hypothesized that modulating this post-translational modification might be more specifically neuroprotective than cell-wide DLK inhibition. To address this possibility, we screened >28,000 compounds using a high-content imaging assay that quantitatively evaluates the palmitoylation-dependent subcellular localization of DLK. Of the 33 hits that significantly altered DLK localization in non-neuronal cells, several reduced DLK retrograde signaling and protected cultured DRG neurons from DLK-dependent neurodegeneration. Mechanistically, the two most neuroprotective compounds selectively prevent stimulus-dependent palmitoylation of axonal pools of DLK, a process crucial for the recruitment of DLK to axonal vesicles. In contrast, these compounds minimally impact DLK localization and signaling in healthy neurons and avoid the cytoskeletal disruption associated with direct DLK inhibition. Importantly, our hit compounds also reduce pro-degenerative retrograde signaling in vivo, suggesting that modulating the palmitoylation-dependent localization of DLK could be a novel neuroprotective strategy.

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Section: Discussionmentioning

confidence: 99%

Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

Zhang,

Jeong,

Niu

et al. 2024

Preprint

View full text Add to dashboard Cite

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Axonal injury signaling is restrained by a spared synaptic branch

Smithson,

Zang,

Junginger

et al. 2024

Preprint

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The intrinsic ability of injured neurons to degenerate and regenerate their axons facilitates nervous system repair, however this ability is not engaged in all neurons and injury locations. Here we investigate the regulation of a conserved axonal injury response pathway with respect to the location of damage in branched motoneuron axons in Drosophila larvae. The dileucine zipper kinase DLK, (also known as MAP3K12 in mammals and Wallenda (Wnd) in Drosophila), is a key regulator of diverse responses to axonal injury. In three different populations of motoneurons, we observed the same striking result that Wnd/DLK signaling becomes activated only in response to injuries that remove all synaptic terminals. Injuries that spare even a small part of a synaptic terminal fail to activate Wnd/DLK signaling, despite the presence of extensive axonal degeneration. The regulation of injury-induced Wnd/DLK signaling occurs independently of its previously known regulator, the Hiw/PHR ubiquitin ligase. We propose that Wnd/DLK signaling regulation is linked to the trafficking of a synapse-to-nucleus axonal cargo and that this mechanism enables neurons to respond to impairments in synaptic connectivity.

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Rab11 suppresses neuronal stress signaling by localizing Dual leucine zipper kinase to axon terminals for protein turnover

Cited by 2 publications

References 89 publications

Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

Axonal injury signaling is restrained by a spared synaptic branch

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