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

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

Research output: Contribution to journalArticle

10 Citations (Scopus)

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

Fingerprint

Nicotinamide Mononucleotide
Nerve Degeneration
NAD
Pharmacology
Nicotinamidase
Axons
Niacin
Spinal Ganglia
Nicotinamide Phosphoribosyltransferase
Neurons
Peripheral Nervous System Diseases
Enzyme Inhibitors

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapyinduced degeneration. / Liu, Hui Wen; Smith, Chadwick B.; Schmidt, Mark S.; Cambronne, Xiaolu; Cohen, Michael; Migaud, Marie E.; Brenner, Charles; Goodman, Richard.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 42, 16.10.2018, p. 10654-10659.

Research output: Contribution to journalArticle

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AU - Cohen, Michael

AU - Migaud, Marie E.

AU - Brenner, Charles

AU - Goodman, Richard

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AB - 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.

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