The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila
- University of Lausanne, Switzerland
- University of Cambridge, United Kingdom
- University Hospital of Geneva, Switzerland
- Polytechnic University of Marche, Italy
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.
Data availability
Generated plasmids have been deposited in Addgene.All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Arnau Llobet Rosell
Giuseppe Orsomando
Lukas Jakob Neukomm
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (176855)
- Lukas Jakob Neukomm
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (211015)
- Lukas Jakob Neukomm
Biotechnology and Biological Sciences Research Council (BB/S009582/1a)
- Jonathan Gilley
International Foundation for Research in Paraplegia (P180)
- Lukas Jakob Neukomm
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (190919)
- Lukas Jakob Neukomm
Università Politecnica delle Marche (2018-20)
- Giuseppe Orsomando
Wellcome Trust (210904/Z/18/Z)
- Andrea Loreto
John and Lucille Van Geest Foundation
- Michael P Coleman
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (201535)
- Pei-Hsuan Wu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Llobet Rosell et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The NAD+ precursor NMN activates dSarm to trigger axon degeneration in Drosophila
eLife 11:e80245.
https://doi.org/10.7554/eLife.80245
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