Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration.

Abstract

Studies of naturally occurring mutant mice, wld(s), 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 Wld(s) protein, the expression of which is responsible for the delayed Wallerian degeneration phenotype in wld(s) 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 Wld(s) protein bearing a W258A mutation, which disrupts NAD-synthesizing activity of the Wld(s) protein. Wallerian degeneration delay in NMNAT3-Tg was similar to that in wld(s) mice, whereas axonal protection in NMNAT1-Tg or Wld(s)(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.

• Authors: Naoki Yahata, Shigeki Yuasa, Toshiyuki Araki
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 19 Pg. 6276-84 (May 13 2009) ISSN: 1529-2401 [Electronic] United States
• PMID: 19439605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Wld protein, mouse
• Adenosine Triphosphate
• Nicotinamide-Nucleotide Adenylyltransferase
• Nmnat1 protein, mouse

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Axons (physiology)
• Electron Transport
• Mice
• Mice, Transgenic
• Mitochondria (enzymology)
• Mutation, Missense
• Nerve Tissue Proteins (genetics, metabolism)
• Neurons (enzymology, physiology)
• Nicotinamide-Nucleotide Adenylyltransferase (genetics, metabolism)
• Sciatic Nerve (injuries, physiopathology)
• Sciatic Neuropathy (physiopathology)
• Wallerian Degeneration (physiopathology)