The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice

doi:10.1073/pnas.0603670103

The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice

Departments of *Neurology and
^¶Pathology and Cell Biology and
^†Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032;
^‡Stokes Research Institute, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; and
^§Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved June 19, 2006 (received for review May 5, 2006)

Abstract

ALS is a fatal paralytic disorder characterized by a progressive loss of spinal cord motor neurons. Herein, we show that NADPH oxidase, the main reactive oxygen species-producing enzyme during inflammation, is activated in spinal cords of ALS patients and in spinal cords in a genetic animal model of this disease. We demonstrate that inactivation of NADPH oxidase in ALS mice delays neurodegeneration and extends survival. We also show that NADPH oxidase-derived oxidant products damage proteins such as insulin-like growth factor 1 (IGF1) receptors, which are located on motor neurons. Our in vivo and in vitro data indicate that such an oxidative modification hinders the IGF1/Akt survival pathway in motor neurons. These findings suggest a non-cell-autonomous mechanism through which inflammation could hasten motor neuron death and contribute to the selective motor neuronal degeneration in ALS.

Footnotes

^‖To whom correspondence should be addressed at:
Departments of Neurology and Pathology, Columbia University, BB-302, 650 West 168th Street, New York, NY 10032.
E-mail: sp30{at}columbia.edu
Author contributions: D.-C.W., D.B.R., H.I., and S.P. designed research; D.-C.W., D.B.R., and M.N. performed research; D.-C.W., D.B.R., M.N., H.I., and S.P. analyzed data; and D.-C.W., D.B.R., H.I., and S.P. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

ROS,

reactive oxygen species;

SOD1,

superoxide dismutase 1;

IGF1,

insulin-like growth factor 1