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In this newsletter, we asked Serge Pzredborski, M.D., Ph.D., to update our readers on his ALS research. Dr. Pzredborski is a clinical neurologist as well as a world-renowned investigator in the mechanisms of neurodegeneration and leads ALS research at the Columbia Health Science Center Amyotrophic lateral sclerosis (ALS) is the most frequent paralytic disorder in adults. Muscle wasting and weakness is due to the progressive loss of brain cells that connect the central nervous system to our muscles. So far, the why and how of this brain cell degeneration remains incompletely understood. Yet, major insights into important questions have started to emerge, thanks to the discovery that mutations in the free radical scavenging enzyme copper/zinc superoxide dismutase (SOD1) gene are associated with a familial form of ALS (FALS). When these mutations are inserted in mice, these animas which now express mutant SOD1 (mSOD1), develop an adult-onset paralytic condition that reproduces the hallmarks of ALS. Remarkably, by using these mice, we and others have found that the level of mSOD1 expression modulates the age of onset of symptoms, but has minimal or no effect on the type of symptoms or the rate of progression of the disease. This suggests that, while mSOD1 is a pivotal factor in the initiation of the disease, additional factors contribute to the progression of the illness. To elucidate such factors, and consequently to develop new therapies aimed at stopping or slowing the progression of ALS, we revisited its neuropathology in search of abnormalities that could shed light on these putative culprits. Interestingly, we found that aside from the dramatic loss of brain cells, which predominates in the spinal cord, there is also a robust glial reaction in both humans and mice with ALS. Although gliosis may, in certain situations, mediate beneficial phenomena, a greater number of situations come to mind in which gliosis may be implicated in harmful events. Given this possibility, we decided to embark on research efforts aimed at identifying glial-derived deleterious factors in human and mouse ALS specimens that could play a meaningful noxious role in this disease. So far, we have identified in human and mouse ALS-diseased spinal cords marked increased expression of the nitric oxide (NO) synthesizing enzyme inducible NO synthase (iNOS) and of the prostaglandin synthesizing enzyme cyclooxygenase type 2 (Cox-2). These two enzymes, by very different mechanisms, may inflict serious damaging effect on brain cells. Indeed, iNOS, by locally producing large amounts of the reactive species nitric oxide (NO), can produce harmful oxidative modifications on proteins and DNA, thus altering the normal cell functioning which ultimately can lead to the demise of this cell. As for Cox-2, this enzyme has emerged as an important determinant of toxicity associated with inflammation. In the normal brain, Cox-2 is significantly expressed only in rare subsets of brain cells. However, under pathological conditions, especially associated with an inflammatory reaction, Cox-2 expression in the brain can increase significantly, as does the level of its products, which are responsible for many of the cytotoxic effects of inflammation. Clearly, these two enzymes may well contribute to the overall disease process in ALS, a possibility that we are actively testing in ALS mice by chronically administering to these animals drugs known to block iNOS and Cox-2. We hope that these ongoing studies will not only confirm that iNOS and Cox-2 are important deleterious factors in ALS, but more importantly that those drugs, by blocking their effects, provide beneficial effects in ALS mice. If confirmed, these investigations may quickly translate into clinical trials in which similar drugs could be tested in ALS patients so that their potential neuroprotective action may be evaluated.
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As we are all still recovering from the unimaginable disaster on September 11th, I hope everyone is safe and well. On behalf of the staff here I express my deep sympathy for those who may have lost their loved ones. While we cannot entirely remove our thoughts from this tragic event, we must get back to our normal life actvities and pay attention to ALS.
