VCP binding influences intracellular distribution of the slow Wallerian degeneration protein, Wld(S)

A. Wilbrey, Jane Haley, T. M. Wishart, L. Conforti, G. Morreale, B. Beirowski, E. Babetto, R. Adalbert, T. H. Gillingwater, T. Smith, D. J. A. Wyllie, R. R. Ribchester, M. P. Coleman

Research output: Contribution to journalArticlepeer-review

Abstract

Wallerian degeneration slow (Wld(S)) mice express a chimeric protein that delays axonal degeneration. The N-terminal domain (N70), which is essential for axonal protection in vivo, binds valosin-containing protein (VCP) and targets both Wld(S) and VCP to discrete nuclear foci. We characterized the formation, composition and localization of these potentially important foci. Missense mutations show that the N-terminal sixteen residues (N16) of Wld(S) are essential for both VCP binding and targeting Wld(S) to nuclear foci. Removing N16 abolishes foci, and VCP binding sequences from ataxin-3 or Will restore them. In vitro, these puncta co-localize with proteasome subunits. In vivo, Wld(S) assumes a range of nuclear distribution patterns, including puncta, and its neuronal expression and intranuclear distribution is region-specific and varies between spontaneous and transgenic Wld(S) models. We conclude that VCP influences Wld(S) intracellular distribution, and thus potentially its function, by binding within the N70 domain required for axon protection.
Original languageEnglish
Pages (from-to)325-340
Number of pages16
JournalMolecular and Cellular Neuroscience
Volume38
Issue number3
DOIs
Publication statusPublished - Jul 2008

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