research paper

Amyotrophic Lateral Sclerosis, a condition that took the life of American baseball hero and Yankee great Lou Gehrig, is the most common form of motor neuron disease. ALS attacks nerve cells and pathways in the brain and spinal cord. Motor neurons reach from the brain through the spine and onto muscles throughout the body. Through these neurons we are able to control all muscle movement, whether it be moving our arms and legs, or simply breathing or opening and closing our eyelids. As ALS progresses and these motor neurons cease to function, our ability to initiate and control muscle movement is lost, ultimately resulting in total paralysis in the later stages of the disease. The average life expectancy for a person with ALS is two to five years from the time of diagnosis. We currently do not know what causes ALS or how it can be prevented and cured. Moreover, only one drug, approved by the FDA in late 1995, currently is available to treat ALS.
Researchers recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS). In addition, Insulin-like growth factor-I (IGF-I) could also be a factor. Due to the effectiveness of IGF-I in the treatment of other diseases and its ability to promote neuronal survival, IGF-I is being extensively studied in ALS therapeutic trials.
The identification in 1993 of superoxide dismutase-1 (SOD1) mutations as the cause of 10 -20% of familial amyotrophic lateral sclerosis cases, prompted a substantial amount of research into the mechanisms of SOD1-mediated toxicity. Recent experiments have demonstrated that oxidation of wild-type SOD1 leads to its misfolding, causing it to gain many of the same toxic properties as mutant SOD1. In vitro studies of oxidized/misfolded SOD1 and in vivo studies of misfolded SOD1 have indicated that these protein species are selectively toxic to motor neurons, suggesting that oxidized/misfolded SOD1 could lead to ALS even in individuals who do not carry an SOD1 mutation. It has also been reported that glial cells secrete oxidized/misfolded mutant SOD1 to the extracellular environment, where it can trigger the selective death of motor neurons, offering a possible explanation for the noncell independent nature of mutant SOD1 toxicity and the rapid progression of disease once the first symptoms develop. Therefore, considering that sporadic (SALS) and familial ALS (FALS) cases are clinically impossible to tell apart, the toxic properties of mutated SOD1 are similar to that of oxidized/misfolded wild-type SOD1 (wtSOD1), and secreted/extracellular misfolded SOD1 is selectively toxic to motor neurons.

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