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How Wld^S neuroprotects

The chimeric WldS protein (top) protects neurons from degrading after insult, and it needs both its domains to do so.

The neuronal guardian protein, Wld^S, like a true superhero, gained its powers by chance mutation. Now, thanks to two studies, we are closer to understanding how Wld^S exerts its protective force.

The slow Wallerian degeneration (Wld^S) protein and its neuroprotective powers came to exist thanks to a spontaneous mutation that fused the genes for Nmnat1 (a NAD⁺ synthesizing enzyme) and Ube4b (a ubiquitination factor). The mutation was discovered by Coleman et al. in 1998 as the reason why a particular mouse strain, described by Hugh Perry a decade earlier, has exceptionally resistant neurons. Given Wld^S's ability, and thus its therapeutic potential for neurodegenerative diseases, it has become the focus of intense scrutiny.

Two groups, Conforti et al. and Avery et al., have now pulled apart Wld^S to learn the secret of its power. They show that both the enzymatic function of Nmnat1 and the ability of the Ube4-derived portion to bind a protein called VCP (or TER94 in flies) are indispensible for Wld^S's neuroprotective effect. VCP is abundant throughout the cell whereas Wld^S localizes primarily to the nucleus. However, when Avery et al. expressed mouse Nmnat3—a relative of Nmnat1 with the same enzyme activity, but that in fly neurons fails to localize to the nucleus—it conferred Wld^S-like protection. Both groups therefore believe that binding of Wld^S to VCP localizes Nmnat1 enzyme function to a region of the cytoplasm it wouldn't normally encounter. The question now is, where. RW

References

Avery, M.A., et al. 2009. J. Cell Biol. 10.1083/jcb.200808042.[Abstract/Free Full Text]

Conforti, L., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200807175.[Abstract/Free Full Text]

ruth.williams{at}rockefeller.edu

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This Article Full Text (PDF, 1190K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, R. Search for Related Content PubMed Articles by Williams, R. Social Bookmarking                            What's this?