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在浦肯野细胞中，MAP3K DLK 和 LZK 的激活会根据信号强度导致快速和缓慢的退化。

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

机构信息

Neurobiology Section, Division of Biological Sciences, University of California San Diego, La Jolla, United States.

Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, United States.

出版信息

Elife. 2021 Jan 21;10:e63509. doi: 10.7554/eLife.63509.

DOI:10.7554/eLife.63509
PMID:33475086
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7870138/
Abstract

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 , 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.

摘要

保守的丝裂原活化蛋白激酶 3 双亮氨酸拉链激酶（DLK）和亮氨酸拉链激酶（LZK）可通过 MKK4 或 MKK7 激活 JNK。这两种 MAP3K 具有相似的生化活性，并在表达增加时发生自动激活。根据细胞类型和损伤的性质，DLK 和 LZK 可以诱导促再生、促凋亡或促退化反应，尽管其作用的机制基础尚不清楚。在这里，我们使用缺失和功能获得的小鼠模型研究了小脑浦肯野细胞中的这两种 MAP3K。虽然缺失每种或两种激酶都不会导致浦肯野细胞明显缺陷，但激活 DLK 会导致快速死亡，激活 LZK 会导致缓慢退化。每种激酶都会独立地诱导 JNK 激活和半胱天冬酶介导的细胞凋亡。重要的是，删除调节 的可变剪接的 CELF2，强烈减弱了由 LZK 引起的浦肯野细胞退化，但不会减弱由 DLK 引起的退化。因此，控制 DLK 和 LZK 的活性水平对神经元的存活和健康至关重要。

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