Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapyinduced degeneration

Hui Wen Liu, Chadwick B. Smith, Mark S. Schmidt, Xiaolu A. Cambronne, Michael S. Cohen, Marie E. Migaud, Charles Brenner, Richard H. Goodman

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1. Some studies challenge this notion, however, and suggest that an aberrant increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN), rather than loss of NAD+, is responsible. In support of this idea, blocking NMN accumulation in neurons by expressing a bacterial NMN deamidase protected axons from degeneration.We hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, we took advantage of an alternative pathway for NAD+ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN. We discovered that nicotinic acid riboside (NAR), a precursor of NAMN, administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN, protected dorsal root ganglion (DRG) axons against vincristineinduced degeneration as well as NMN deamidase. Introducing a different bacterial enzyme that converts NAMN to NMN reversed this protection. Collectively, our data indicate that maintaining NAD+ is not sufficient to protect DRG neurons from vincristineinduced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.

Original languageEnglish (US)
Pages (from-to)10654-10659
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number42
DOIs
StatePublished - Oct 16 2018

Keywords

  • Axon degeneration
  • Chemotherapy-induced peripheral neuropathy
  • NAD+
  • Nicotinamide mononucleotide
  • Nicotinic acid riboside

ASJC Scopus subject areas

  • General

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