Mutations in the cytosolic enzyme, superoxide dismutase 1, have been identified as the cause of motor neuron disease in a subset of cases of familial amyotrophic lateral sclerosis. It has been postulated that the injurious property of mutant enzyme resides in its propensity to aggregate or its propensity to catalyze deleterious, copper-mediated, chemistries. Aggregates of SOD1 have been identified, histologically, in neurons and astroglia of the spinal cords of SOD1-linked FALS patients and in transgenic mice that express these mutant proteins. In the present study, we have employed a technique used in detecting and quantifying aggregates of mutant huntingtin (cellulose acetate filtration) to examine the molecular characteristics of mutant SOD1 in three previously characterized transgenic mouse models of FALS. We show that the brains and spinal cords of these mice accumulate mutant SOD1 complexes that can be trapped by cellulose acetate filtration. The relative abundance of these structures increases dramatically with age. Although expressed to the same level in nonnervous tissues, mutant SOD1 was not found in high molecular weight structures. We conclude that some aspect of the biology of neural tissues (in a setting of declining motor neuron function) predisposes to the accumulation of high molecular weight complexes of mutant SOD1.
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