Molecular mechanism of axonal degeneration

Toshiyuki Araki, Shuji Wakatsuki

Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry

Axonal degeneration is an active process of structural degradation, involving cascades of subcellular signaling and enzymatic reactions. We previously reported ZNRF1, an E3 ligase, promotes Wallerian degeneration by targeting Akt to degrade via the ubiquitin-proteasome system. Akt phosphorylates glycogen synthase kinase (GSK)3B, and thereby inactivates it in axons. Active form of GSK3B induces CRMP2 phosphorylation, which is required for the microtubule reorganization observed in the degenerating axon. In a recent report, we demonstrated that oxidative stress serves as an activator of ZNRF1 by inducing EGFR-mediated phosphorylation at the 103rd tyrosine residue, and that the up-regulation of ZNRF1 activity by oxidative stress leads to neuronal apoptosis and Wallerian degeneration. A deeper understanding of the regulatory mechanism for ZNRF1 catalytic activity via phosphorylation will provide a potential therapeutic avenue for neurodegeneration.

Address correspondence to Dr. Toshiyuki Araki, 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)