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Chronically Low NMNAT2 Expression Causes Sub-lethal SARM1 Activation and Altered Response to Nicotinamide Riboside in

Christina Antoniou1, Andrea Loreto1,2, Jonathan Gilley1

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Low levels of Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) trigger sub-lethal SARM1 activation, impairing axon health and NAD(P) levels. This SARM1-dependent effect may predispose individuals to axonal disorders.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is crucial for axon survival, inhibiting the pro-degenerative protein SARM1.
  • Complete NMNAT2 deficiency causes severe axon defects and lethality in mice, which are rescued by SARM1 removal.
  • Sub-heterozygous NMNAT2 levels are compatible with life but lead to axonal defects and behavioral phenotypes.

Purpose of the Study:

  • To investigate the impact of chronically low NMNAT2 expression on SARM1 activation and disease susceptibility.
  • To determine if reduced NMNAT2 levels trigger SARM1 activation in otherwise intact axons.
  • To explore the consequences of low NMNAT2 on NAD(P) levels and response to NAD+ precursors.

Main Methods:

  • Utilized mouse models with varying NMNAT2 expression levels.
  • Examined prenatal viability and SARM1-dependent phenotypes.
  • Assessed SARM1 activation in superior cervical ganglion (SCG) primary cultures.
  • Measured NAD(P) levels and neurite outgrowth.
  • Investigated the interaction with nicotinamide riboside (NR) supplementation.

Main Results:

  • Chronically low NMNAT2 levels reduced prenatal viability in a SARM1-dependent manner.
  • Sub-lethal SARM1 activation was observed in SCG cultures with low NMNAT2.
  • Axonal NAD(P) depletion and compromised neurite outgrowth were associated with low NMNAT2.
  • Low NMNAT2 reversed the NAD-enhancing effects of NR in axons, dependent on SARM1.

Conclusions:

  • Low NMNAT2 levels can initiate sub-lethal SARM1 activation, detectable at the molecular level.
  • This molecular activation compromises axon health and NAD(P) homeostasis.
  • These findings suggest a potential link between reduced NMNAT2 and predisposition to human axonal disorders.