Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength
| Autor: | Christopher L Steinke, Yishi Jin, Lizhen Chen, Erin M Ritchie, Yunbo Li, Cai Qi, Binhai Zheng |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Celf2 Cerebellum Mouse cerebellum Cell Survival QH301-705.5 1.1 Normal biological development and functioning Science Purkinje cell Degeneration (medical) General Biochemistry Genetics and Molecular Biology neuroscience 03 medical and health sciences Mice 0302 clinical medicine Underpinning research medicine Animals Biology (General) mouse General Immunology and Microbiology MAP kinase kinase kinase Chemistry Kinase General Neuroscience Neurodegeneration Alternative splicing Neurosciences neurodegeneration General Medicine medicine.disease MAP Kinase Kinase Kinases Cell biology LZK 030104 developmental biology medicine.anatomical_structure Apoptosis Purkinje cells Medicine Biochemistry and Cell Biology 030217 neurology & neurosurgery DLK Signal Transduction Research Article Neuroscience |
| Zdroj: | eLife, Vol 10 (2021) eLife |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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