Elsevier

Neuroscience Letters

Volume 411, Issue 3, 16 January 2007, Pages 228-232
Neuroscience Letters

Protection of vincristine-induced neuropathy by WldS expression and the independence of the activity of Nmnat1

https://doi.org/10.1016/j.neulet.2006.09.068Get rights and content

Abstract

The slow Wallerian degeneration protein (WldS), a fusion protein containing amino-terminal E4B and full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by physical damages, toxins and genetic mutations which result in patients being diagnosed with neurodegenerative diseases. It is still controversial whether the suppression of axonal degeneration by WldS is due to Nmnat1 or other portion. We generated WldS or Nmnat1-overexpressing Neuro2A cell lines, in which neuronal differentiation including neurite elongation can be induced by retinoic acid. The overexpression of WldS delayed the neurite degeneration by vincristine, whereas that of Nmnat1 did not delay it much. Taken together, Nmnat1 is considerably weaker than WldS for protection from toxic injury in vitro, suggesting that amino-terminal region of WldS is likely to be more significant for protection from axonal degeneration.

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Acknowledgements

We thank G. Wilmot and T. Kitamura for the plasmids and cell lines and Y. Soida for her help in preparing the manuscript. This work was supported in part by a research grant from Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology (18023003, 18659252) and the General Insurance Association of Japan.

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      Several attempts have been made to transfer the neuroprotective benefits of WldS expression to animal models of neurodegenerative disease, with variable success. Crossbreeding WldS mice with models of peripheral neuropathy or axonopathy disease mitigates the onset and progression of disease signs (Wang et al., 2001, 2002; Ferri et al., 2003; Samsam et al., 2003; Watanabe et al., 2007; Meyer zu Horste et al., 2011). However, not all models of neurodegeneration are protected by co-expression of WldS (Vande Velde et al., 2004; Fischer et al., 2005; Kariya et al., 2009).

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      Similarly VDAC1 is a known component of the NAD pathway, affecting cellular equilibrium via maintenance of cellular redox homeostasis (55). NAD levels, which can be manipulated by changing expression levels of Nmnat1, have been shown previously to at least partially replicate the Wlds phenotype in vitro (Refs. 21–23, but see Refs. 24 and 25). It is possible, therefore, that NAD-mediated neuroprotection of non-somatic compartments may be acting through modulating Aralar1 and/or VDAC1 levels.

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