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

Published ineLife, vol. 11, e80245
Publication date2022-12-07
First online date2022-12-07
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 inDrosophilathrough 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 unchangedin 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 degenerationin 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 inDrosophila.

Keywords
  • D. melanogaster
  • Cell biology
  • Neuroscience
Citation (ISO format)
LLOBET ROSELL, Arnau et al. The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila. In: eLife, 2022, vol. 11, p. e80245. doi: 10.7554/eLife.80245
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Article (Accepted version)
Identifiers
Journal ISSN2050-084X
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203downloads

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Creation19/12/2022 10:31:00
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