Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress

J Neurosci. 2008 May 7;28(19):4861-71. doi: 10.1523/JNEUROSCI.0525-08.2008.

Abstract

Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld(s) mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wld(s) mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wld(s) mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat-mediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Axons / drug effects*
  • Cells, Cultured
  • Down-Regulation
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / embryology
  • Gene Transfer Techniques
  • Isoenzymes / genetics
  • Isoenzymes / pharmacology
  • Mitochondrial Diseases / complications*
  • Nerve Degeneration / chemically induced
  • Nerve Degeneration / etiology*
  • Nerve Degeneration / prevention & control*
  • Neurons / metabolism
  • Nicotinamide-Nucleotide Adenylyltransferase / genetics
  • Nicotinamide-Nucleotide Adenylyltransferase / pharmacology*
  • Oxidative Stress* / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Rotenone
  • Stress, Physiological / complications
  • Vincristine / pharmacology

Substances

  • Antioxidants
  • Isoenzymes
  • Rotenone
  • Vincristine
  • Adenosine Triphosphate
  • NMNAT1 protein, rat
  • NMNAT3 protein, rat
  • Nicotinamide-Nucleotide Adenylyltransferase