Mechanisms of Cell Death in ALS Serge Przedborski, MD, PhD recipient of the AAN Sheila Essey Award for ALS Research in 2002, recently presented at Columbia’s MDA/ALS Support Group at All Souls Church in New York City. Dr. Przedborski’s research efforts are aimed at elucidating the mechanisms of neuronal cell death in ALS. Following are some of the points that he related: SOD is an enzyme that protects us from the potential damage of oxidative stress due to substances called "free radicals" in our bodies. ALS seems to progress in an organized fashion, rather than randomly: nerve cells that are in closest proximity to each other get damaged in a ripple pattern. It is understood that mutated SOD proteins start the disease process in patients with familial ALS. It is the identified ALS2 gene that produces another familial form of ALS, but it is a recessive trait (i.e., both parents are the carriers of the abnormal gene and the patient must have the two abnormal genes for the disease to express) Once SOD starts mutating, several other mechanisms get triggered: Oxidative stress goes uncontrolled Glutamate toxicity Aggregation (clumping together) of mutant proteins Apoptosis means "cell suicide." Apoptosis is normally repressed. When apoptosis is in an abnormal state, and repressive function is "lifted," cells die by killing themselves. The cascade of cell death events was described. If we could interfere much earlier than the "caspase" part of the cascade, cell death could be stopped. Therefore, a "caspase" intervention is too late in the cascade. What is earlier in the cascade? Inflammation. Cancer represents a "synchronous cell death process." ALS is "asynchronous." However, some processes are similar, like inflammation. Minocycline blocks astrocyte cells, which allow free radicals and nitrous oxide to go unmonitored in the body. Cox-2 inhibitors also seem to help eliminate pro-inflammatory factors, which would in turn slow the progression of cell death. There is a strong indication that if we understand the mechanisms of the cell death process in familial SOD1 mutation, we will unravel the mystery of sporadic ALS, because the cell death process may be the same.