Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content Screening View Full Text


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Article Info

DATE

2019-12

AUTHORS

Dale D. O. Martin, Prasad S. Kanuparthi, Sabrina M. Holland, Shaun S. Sanders, Hey-Kyeong Jeong, Margret B. Einarson, Marlene A. Jacobson, Gareth M. Thomas

ABSTRACT

After axonal insult and injury, Dual leucine-zipper kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). We recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay. Here we report that DLK subcellular localization in non-neuronal cells is highly palmitoylation-dependent and can thus serve as a proxy readout to identify inhibitors of DLK palmitoylation by High Content Screening (HCS). We optimized an HCS assay based on this readout, which showed highly robust performance in a 96-well format. Using this assay we screened a library of 1200 FDA-approved compounds and found that ketoconazole, the compound that most dramatically affected DLK localization in our primary screen, dose-dependently inhibited DLK palmitoylation in follow-up biochemical assays. Moreover, ketoconazole significantly blunted phosphorylation of c-Jun in primary sensory neurons subjected to trophic deprivation, a well known model of DLK-dependent pro-degenerative signaling. Our HCS platform is thus capable of identifying novel inhibitors of DLK palmitoylation and signalling that may have considerable therapeutic potential. More... »

PAGES

3632

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-39968-8

DOI

http://dx.doi.org/10.1038/s41598-019-39968-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112580745

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30842471


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