Transgenic mice expressing the nmnatl protein manifest robust delay in axonal degeneration in vivo

Yo Sasaki, Bhupinder P.S. Vohra, Robert H. Baloh, Jeffrey Milbrandt

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

Axonal degeneration is a key component of a variety of neurological diseases. Studies using wld s mutant mice have demonstrated that delaying axonal degeneration slows disease course and prolongs survival in neurodegenerative disease models. The Wld s protein is normally localized to the nucleus, and contains the N terminus of ubiquitination factor Ube4b fused to full-length Nmnatl, an NAD biosynthetic enzyme. While Nmnat enzymatic activity is necessary for Wld s-mediated axonal protection, several important questions remain including whether the Ube4b component of WIl s 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 cytNmnatl, an engineered mutant of Nmnatl localized only to the cytoplasm and axon, that provides more potent axonal protection than that afforded by WId8 or Nmnatl, we generated transgenic mice using the prion protein promoter (PrP). The sciatic nerve of these cytNmnatl 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 Wld s 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.

Original languageEnglish
Pages (from-to)6526-6534
Number of pages9
JournalJournal of Neuroscience
Volume29
Issue number20
DOIs
StatePublished - May 20 2009

Fingerprint Dive into the research topics of 'Transgenic mice expressing the nmnatl protein manifest robust delay in axonal degeneration in vivo'. Together they form a unique fingerprint.

  • Cite this