AGGREGATION OF MUTANT CU ZN SUPEROXIDE-DISMUTASE PROTEINS IN A CULTURE MODEL OF ALS/

Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis (FALS), a neurodegene rative disorder characterized by loss of cortical, brainstem, and spin al motor neurons. To investigate the mechanisms responsible for the to xicity of mutant enzyme, SOD-1 cDNAs bearing mutations found in FALS p atients (mSOD) were expressed in cultured spinal motor neurons, dorsal root ganglion (DRG) and hippocampal neurons. Many features of motor n euron disease seen in humans with FALS and in transgenic mouse models were reproduced, including preferential susceptibility of motor neuron s to toxicity of mSOD. Abnormal cytoplasmic aggregation of mSOD protei n was observed in mSOD-expressing motor neurons, but never in neurons expressing SODwt enzyme, and was followed by evidence of apoptotic cel l death. Such aggregates were not observed in nonvulnerable neuronal p opulations expressing mSOD (DRG or hippocampal neurons). Aggregation o f SOD-1 may contribute significantly to the death of motor neurons exp ressing mutations associated with FALS-1 and the mechanisms leading to aggregation may pertain to the specific vulnerability of motor neuron s in this disease.