Inflammatory Enzyme Affects Motor Neuron Damage in Amyotrophic Lateral Sclerosis

Serge Przedborski, MD, Ph.D.
Departments of Neurology and Pathology, Columbia University
R01ES13177

Serge Przedborski of Columbia University reported in the August 8 edition of the Proceedings of the National Academy of Sciences new insights in the death of motor neurons resulting from amyotrophic lateral sclerosis. Przedborski has been a pioneer in the investigation of the molecular mechanisms leading to the death of neurons that occurs in ALS and Parkinson's disease.

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease for the legendary New York Yankee first baseman who died of the disease in 1941, is a progressive neuromuscular disease that weakens and eventually destroys motor neurons that connect the brain with the skeletal muscles. Patients gradually lose the ability to speak, swallow, and move voluntarily. Sensory function and intellectual ability are unaffected and death usually results from loss of respiratory function. Approximately 30,000 patients in the United States currently have ALS. The disease has no racial, socioeconomic, or ethnic boundaries. The life expectancy of ALS patients is usually three to five years after diagnosis. ALS is most commonly diagnosed in middle age and affects men more often than women.

The researchers discovered that an enzyme known as NADPH oxidase, an important component in the generation of destructive reactive oxygen species during inflammation, is active in the spinal cords of ALS patients and also in a mouse model of the disease. When the researchers inactivated the enzyme in the mice, neurodegeneration was significantly delayed and the mice lived longer. Additional studies also showed that NADPH-oxidase-derived oxidative products also damaged proteins including insulin-like growth factor 1 (IGF-1) receptors located on motor neurons. IGF1 has been demonstrated to have therapeutic potential in ALS patients. These results suggest that co-administration an anti-inflammatory agent may improve the therapeutic response of IGF1 in ALS patients.

Citation: Wu DC, Re DB, Nagai M, Ischiropoulos H, Przedborski S. The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12132-7.