Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength

eLife

Yishi Jin¹  Binhai Zheng²  Lizhen Chen³  Christopher L Steinke³  Yunbo Li³  Erin M Ritchie³  Cai Qi³ 

[1] VA San Diego Healthcare System, San Diego, United States;Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, United States;Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, United States;

关键词: Purkinje cells;    cerebellum;    DLK;    LZK;    Celf2;    neurodegeneration;   

DOI  :  10.7554/eLife.63509

来源: DOAJ

【 摘 要 】

The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. 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. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. 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. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

【 授权许可】

Unknown