Maintaining energy homeostasis is an essential component of WldS-mediated axon protection

Hua Shen, Krzysztof L. Hyrc, Mark P. Goldberg

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

WldS mutation protects axons from degeneration in diverse experimental models of neurological disorders, suggesting that the mutation might act on a key step shared by different axon degeneration pathways. Here we test the hypothesis that WldS protects axons by preventing energy deficiency commonly encountered in many diseases. We subjected compartmentally cultured, mouse cortical axons to energy deprivation with 6mM azide and zero glucose. In wild-type (WT) culture, the treatment, which reduced axon ATP level ([ATP]axon) by 65%, caused immediate axon depolarization followed by gradual free calcium accumulation and subsequent irreversible axon damage. The calcium accumulation resulted from calcium influx partially via L-type voltage-gated calcium channel (L-VGCC). Blocking L-VGCC with nimodipine reduced calcium accumulation and protected axons. Without altering baseline [ATP]axon, the presence of WldS mutation significantly reduced the axon ATP loss and depolarization, restrained the subsequent calcium accumulation, and protected axons against energy deprivation. WldS neurons possessed higher than normal nicotinamide mononucleotide adenylyltransferase (NMNAT) activity. The intrinsic WldS NMNAT activity was required for the WldS-mediated energy preservation and axon protection during but not prior to energy deprivation. NMNAT catalyzes the reversible reaction that produces nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide (NMN). Interestingly, preventing the production of NAD from NMN with FK866 increased [ATP]axon and protected axons from energy deprivation. These results indicate that the WldS mutation depends on its intrinsic WldS NMNAT activity and the subsequent increase in axon ATP but not NAD to protect axons, implicating a novel role of WldS NMNAT in axon bioenergetics and protection.

Original languageEnglish (US)
Pages (from-to)69-79
Number of pages11
JournalNeurobiology of Disease
Volume59
DOIs
StatePublished - Nov 2013

Keywords

  • ATP
  • Axon injury
  • Bioenergetics
  • Calcium
  • Energy deprivation
  • NMNAT
  • Wld

ASJC Scopus subject areas

  • Neurology

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