期刊
NATURE CELL BIOLOGY
卷 13, 期 12, 页码 1415-U259出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2373
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资金
- Ministry of Health, Labour, and Welfare
- NIBIO (Program for Promotion of Fundamental Studies in Health Sciences)
- Japan Foundation for Neuroscience and Mental Health
- Japan Health Sciences Foundation
- NICHD
- Grants-in-Aid for Scientific Research [23700462] Funding Source: KAKEN
Wallerian degeneration is observed in many neurological disorders, and it is therefore important to elucidate the axonal degeneration mechanism to prevent, and further develop treatment for, such diseases. The ubiquitin proteasome system (UPS) has been implicated in Wallerian degeneration, but the underlying molecular mechanism remains unclear. Here we show that ZNRF1, an E3 ligase, promotes Wallerian degeneration by targeting AKT to degrade through the UPS. AKT phosphorylates glycogen synthase kinase-3 beta (GSK3B), and thereby inactivates it in axons. AKT overexpression significantly delays axonal degeneration. Overexpression of the active (non-phosphorylated) form of GSK3B induces CRMP2 phosphorylation, which is required for the microtubule reorganization observed in the degenerating axon. The inhibition of GSK3B and the overexpression of non-phosphorylated CRMP2 both protected axons from Wallerian degeneration. These findings indicate that the ZNRF1 AKT GSK3B CRMP2 pathway plays an important role in controlling Wallerian degeneration.
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