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- Title
Transgenic Mice Expressing the Nmnat1 Protein Manifest Robust Delay in Axonal Degeneration In Vivo.
- Authors
Sasaki, Yo; Vohra, Bhupinder P. S.; Baloh, Robert H.; Milbrandt, Jeffrey
- Abstract
Axonal degeneration is a key component of a variety of neurological diseases. Studies using wlds mutant mice have demonstrated that delaying axonal degeneration slows disease course and prolongs survival in neurodegenerative disease models. The Wlds protein is normally localized to the nucleus, and contains the N terminus of ubiquitination factor Ube4b fused to full-length Nmnat1, an NAD biosynthetic enzyme. While Nmnat enzymatic activity is necessary for Wlds-mediated axonal protection, several important questions remain including whether the Ube4b component of Wlds also plays a role, and in which cellular compartment (nucleus vs cytosol) the axonal protective effects of Nmnat activity are mediated. While Nmnat alone is clearly sufficient to delay axonal degeneration in cultured neurons, we sought to determine whether it was also sufficient to promote axonal protection in vivo. Using cytNmnat1, an engineered mutant of Nmnat1 localized only to the cytoplasm and axon, that provides more potent axonal protection than that afforded by Wlds or Nmnat1, we generated transgenic mice using the prion protein promoter (PrP). The sciatic nerve of these cytNmnat1 transgenic mice was transected, and microscopic analysis of the distal nerve segment 7 d later revealed no evidence of axonal loss or myelin debris, indicating that Nmnat alone, without any other Wlds sequences, is all that is required to delay axonal degeneration in vivo. These results highlight the importance of understanding the mechanism of Nmnat-mediated axonal protection for the development of new treatment strategies for neurological disorders.
- Subjects
TRANSGENIC mice; AXONAL transport; NEURODEGENERATION; MYELIN proteins; CELL nuclei; CYTOSOL
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 20, p6526
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1429-09.2009