Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress

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J Neurosci. 2008 May 7;28(19):4861-71.

Nmnat delays axonal degeneration caused by mitochondrial and

oxidative stress.

Press C, Milbrandt J.

Department of Pathology, Hope Center for Neurological Disorders,

Washington University School of Medicine, St. Louis, Missouri 63110,

USA.

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.

About Rotenone: http://en.wikipedia.org/wiki/Rotenone