The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila

Elife. 2022 Dec 23:11:e80245. doi: 10.7554/eLife.80245.

Abstract

Axon degeneration contributes to the disruption of neuronal circuit function in diseased and injured nervous systems. Severed axons degenerate following the activation of an evolutionarily conserved signaling pathway, which culminates in the activation of SARM1 in mammals to execute the pathological depletion of the metabolite NAD+. SARM1 NADase activity is activated by the NAD+ precursor nicotinamide mononucleotide (NMN). In mammals, keeping NMN levels low potently preserves axons after injury. However, it remains unclear whether NMN is also a key mediator of axon degeneration and dSarm activation in flies. Here, we demonstrate that lowering NMN levels in Drosophila through the expression of a newly generated prokaryotic NMN-Deamidase (NMN-D) preserves severed axons for months and keeps them circuit-integrated for weeks. NMN-D alters the NAD+ metabolic flux by lowering NMN, while NAD+ remains unchanged in vivo. Increased NMN synthesis by the expression of mouse nicotinamide phosphoribosyltransferase (mNAMPT) leads to faster axon degeneration after injury. We also show that NMN-induced activation of dSarm mediates axon degeneration in vivo. Finally, NMN-D delays neurodegeneration caused by loss of the sole NMN-consuming and NAD+-synthesizing enzyme dNmnat. Our results reveal a critical role for NMN in neurodegeneration in the fly, which extends beyond axonal injury. The potent neuroprotection by reducing NMN levels is similar to the interference with other essential mediators of axon degeneration in Drosophila.

Keywords: D. melanogaster; NAD metabolism; axon degeneration; cell biology; genetics; neurodegeneration; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Axons / physiology
  • Cytoskeletal Proteins / metabolism
  • Drosophila* / metabolism
  • Mammals / metabolism
  • Mice
  • NAD / metabolism
  • Neurons / physiology
  • Nicotinamide Mononucleotide* / metabolism

Substances

  • Nicotinamide Mononucleotide
  • NAD
  • SARM1 protein, mouse
  • Cytoskeletal Proteins
  • Armadillo Domain Proteins