elegans DLK-1 and Drosophila DLK/Wallenda ( Jin and Zheng, 2019).

The mammalian MAP3K DLK (Dual leucine zipper kinase, or MAP3K12) and LZK (Leucine zipper kinase, or MAP3K13) are orthologs of C. The MAPK cascade involves MAP3Ks (MAP kinase kinase kinases), MAP2Ks and MAPKs that together form a phosphorylation relay and activate downstream signaling events in response to external or internal stimuli. Mitogen-activated protein kinase (MAPK) signaling pathways play important roles in neuronal development and function, and aberrant regulation of MAP kinases is associated with many neurological diseases, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) ( Thomas and Huganir, 2004 Schellino et al., 2019 Hotamisligil and Davis, 2016 Hollville et al., 2019 Asghari Adib et al., 2018).

Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7.

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