Prevention of mutant SOD1 motoneuron degeneration by copper chelators in vitro

An animal model of familial amyotrophic lateral sclerosis (FALS) has been g enerated by overexpression of human CuZn superoxide dismutase (SOD1) contai ning a substitution of glycine to alanine at position 93 in transgenic G93A mice, The loss of motoneurons shown in this model has been attributed to a dominant gain of function of this mutated enzyme, which might be due to co pper toxicity. This hypothesis was tested in purified spinal motoneurons cu ltures originating from G93A transgenic embryos. Spinal motoneurons were is olated from E13 embryos by several steps including density gradient centrif ugation. The effect of copper chelators on survival and neurite growth of m otoneurons was investigated. Survival of G93A motoneurons was decreased by 46% as compared to wild-type motoneurons. Moreover, G93A motoneurons showed reduced neurite outgrowth, Copper chelators strikingly increased viability of G93A motoneurons (by over 200%) but had no effect on wild-type cells. P resence of DDC in the medium increases the length of neurites from G93A mot oneurons, The present results suggest the capacity of copper chelators to r educe the effect of reverse function of mutated SOD1 on motoneurons. (C) 20 00 John Wiley & Sons, Inc.