Deletion of Nampt in Projection Neurons of Adult Mice Leads to Motor Dysfunction, Neurodegeneration, and Death

Xiaowan Wang, Qiao Zhang, Ruisi Bao, Nannan Zhang, Yingzhen Wang, Luis Polo-Parada, Andrew Tarim, Aidan Alemifar, Xianlin Han, Heather M. Wilkins, Russell H. Swerdlow, Xinglong Wang, Shinghua Ding

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD+ biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs). When treated with nicotinamide mononucleotide (NMN), Nampt cKO mice exhibit reduced motor function deficits and prolonged lifespan. iNAMPT protein levels are significantly reduced in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, indicating the involvement of NAMPT in ALS pathology. Our findings reveal that neuronal NAMPT plays an essential role in mitochondrial bioenergetics, motor function, and survival. Our study suggests that the NAMPT-mediated NAD+ biosynthesis pathway is a potential therapeutic target for degenerative MN diseases.

Original languageEnglish (US)
Pages (from-to)2184-2200
Number of pages17
JournalCell Reports
Volume20
Issue number9
DOIs
StatePublished - Aug 29 2017

Keywords

  • ALS
  • MN degeneration
  • NAD
  • NMJ abnormalities
  • evoked endplate potential
  • hyperacetylation
  • mitochondrial function
  • motor function deficits
  • nicotinamide mononucleotide
  • projection neurons

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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