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ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation

Nature Cell Biology volume 13, pages 1415–1423 (2011)Cite this article

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Abstract

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-3β (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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Figure 1: Role of AKT and GSK3B during Wallerian degeneration.
Figure 2: ZNRF1 targets AKT for proteasomal degradation.
Figure 3: Inhibition of the ZNRF1–AKT–GSK3B pathway delays Wallerian degeneration.
Figure 4: CRMP2 phosphorylation is a critical event downstream of GSK3B activation during Wallerian degeneration.
Figure 5: Inhibition of the ZNRF1–AKT–GSK3B–CRMP2 pathway delays axonal degeneration of optic nerves in vivo.
Figure 6: ZNRF1–AKT–GSK3B–CRMP2 maintains axonal integrity downstream of the mechanism for WLDS-protein-dependent axonal protection.

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Acknowledgements

The authors would like to thank N. Matsuda and H. Yashiroda for technical advice and all members of our laboratory for many helpful discussions. This study is supported by grants from the Ministry of Health, Labour, and Welfare (T.A.), NIBIO (Program for Promotion of Fundamental Studies in Health Sciences; T.A.), Japan Foundation for Neuroscience and Mental Health (T.A. and S.W.) and Japan Health Sciences Foundation (T.A. and S.W.). The E7, 2H3 and 9E10 antibody clones developed by M. Klymkowsky, T. Jessel and J. Dodd, and J. Bishop, respectively, were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the Department of Biology, The University of Iowa, USA.

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  1. Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan

    Shuji Wakatsuki, Fuminori Saitoh & Toshiyuki Araki

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  1. Shuji Wakatsuki
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  3. Toshiyuki Araki
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S.W. and T.A. designed the experiments, analysed the data and wrote the manuscript. S.W. carried out the experiments, collected the data and prepared the figures. F.S. provided the reagents and technical support. T.A. directed and planned the project.

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Correspondence to Toshiyuki Araki.

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The authors declare no competing financial interests.

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Wakatsuki, S., Saitoh, F. & Araki, T. ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol 13, 1415–1423 (2011). https://doi.org/10.1038/ncb2373

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