Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration

Naoki Yahata, Shigeki Yuasa, Toshiyuki Araki

研究成果: Article査読

131 被引用数 (Scopus)


Studies of naturally occurring mutant mice, wlds, showing delayed Wallerian degeneration phenotype, suggest that axonal degeneration is an active process.We previously showed that increased nicotinamide adenine dinucleotide (NAD)-synthesizing activity by overexpression of nicotinamide mononucleotide adenylyltransferase (NMNAT) is the essential component of the Wlds protein, the expression of which is responsible for the delayed Wallerian degeneration phenotype in wlds mice. Indeed, NMNAT overexpression in cultured neurons provides robust protection to neurites, as well. To examine the effect of NMNAT overexpression in vivo and to analyze the mechanism that causes axonal protection, we generated transgenic mice (Tg) overexpressing NMNAT1 (nuclear isoform), NMNAT3 (mitochondrial isoform), or the Wlds protein bearing a W258A mutation, which disrupts NAD-synthesizing activity of the Wlds protein. Wallerian degeneration delay in NMNAT3-Tg was similar to that in wlds mice, whereas axonal protection in NMNAT1-Tg or Wlds(W258A)-Tg was not detectable. Detailed analysis of subcellular localization of the overexpressed proteins revealed that the axonal protection phenotype was correlated with localization of NMNAT enzymatic activity to mitochondrial matrix. Furthermore, we found that isolated mitochondria from mice showing axonal protection expressed unchanged levels of respiratory chain components, but were capable of increased ATP production. These results suggest that axonal protection by NMNAT expression in neurons is provided by modifying mitochondrial function. Alteration of mitochondrial function may constitute a novel tool for axonal protection, as well as a possible treatment of diseases involving axonopathy.

ジャーナルJournal of Neuroscience
出版ステータスPublished - 13-05-2009

All Science Journal Classification (ASJC) codes

  • 神経科学(全般)


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