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Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (Nmnat) protein transduction into transected axons.

ABSTRACT: Axonal degeneration is an early and important component of many neurological disorders. Overexpression of nicotinamide mononucleotide adenylyltransferase (Nmnat), a component of the slow Wallerian degeneration (Wld(s)) protein, protects axons from a variety of insults. We found that transduction of Nmnat protein into severed axons via virus-like particles prevented axonal degeneration. The post-injury efficacy of Nmnat indicates that its protective effects occur locally within the axon and provides an opportunity to develop novel agents to treat axonal damage.

SUBMITTER: Sasaki Y

PROVIDER: S-EPMC3009846 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Axonal degeneration is blocked by nicotinamide mononucleotide adenylyltransferase (Nmnat) protein transduction into transected axons.

Sasaki Yo Y Milbrandt Jeffrey J

The Journal of biological chemistry 20101111 53

Axonal degeneration is an early and important component of many neurological disorders. Overexpression of nicotinamide mononucleotide adenylyltransferase (Nmnat), a component of the slow Wallerian degeneration (Wld(s)) protein, protects axons from a variety of insults. We found that transduction of Nmnat protein into severed axons via virus-like particles prevented axonal degeneration. The post-injury efficacy of Nmnat indicates that its protective effects occur locally within the axon and provi ...[more]

PMID: 21071441

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Nicotinamide mononucleotide adenylyltransferase expression in mitochondrial matrix delays Wallerian degeneration.

Project description: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.

| S-EPMC6665489 | biostudies-literature

Amyloid precursor protein cleavage-dependent and -independent axonal degeneration programs share a common nicotinamide mononucleotide adenylyltransferase 1-sensitive pathway.

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Nicotinamide mononucleotide adenylyltransferase displays alternate binding modes for nicotinamide nucleotides.

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Identification of a nicotinamide/nicotinate mononucleotide adenylyltransferase in Giardia lamblia (GlNMNAT).

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| S-EPMC9108885 | biostudies-literature

The NAD+ synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) regulates ribosomal RNA transcription.

Project description:The chromosomal region encoding the nuclear NAD(+) synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) is frequently deleted in human cancer. We describe evidence that NMNAT1 interacts with the nucleolar repressor protein nucleomethylin and is involved in regulating rRNA transcription. NMNAT1 binds to nucleomethylin and is recruited into a ternary complex containing the NAD(+)-dependent deacetylase SirT1. NMNAT1 expression stimulates the deacetylase function of SirT1. Knockdown of NMNAT1 enhances rRNA transcription and promotes cell death after nutrient deprivation. Furthermore, NMNAT1 expression is induced by DNA damage and plays a role in preventing cell death after damage. Heterozygous deletion of NMNAT1 in lung tumor cell lines correlates with low expression level and increased sensitivity to DNA damage. These results suggest that NMNAT1 deletion in tumors may contribute to transformation by increasing rRNA synthesis, but may also increase sensitivity to nutrient stress and DNA damage.

| S-EPMC3774361 | biostudies-literature

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