MUTATIONS IN SOD1 ASSOCIATED WITH AMYOTROPHIC-LATERAL-SCLEROSIS CAUSENOVEL PROTEIN INTERACTIONS

A subset of familial and sporadic amyotrophic lateral sclerosis (ALS - a fatal disorder characterised by progressive motor neuron degenerati on) cases are due to mutations in the gene encoding Cu,Zn superoxide d ismutase (SOD1)(1-4). Two mutations which have been successfully used to generate transgenic mice that develop an ALS-like syndrome are glyc ine 85 to arginine (G85R) and glycine 93 to alanine (G93A) with the mu tant SOD1 allele overexpressed in a normal mouse genetic background(5- 7). No ALS-like phenotype is observed in mice overexpressing wild-type SOD1 or mice without any SOD1 activity(6,8,9). These dominant mutatio ns, which do not necessarily decrease SOD1 activity, may confer a gain of function that is selectively lethal to motor neurons(5,10-12). The yeast interaction trap system(13) allowed us to determine whether the se mutations in SOD1 caused novel protein interactions not observed wi th wild-type SOD1 and which might participate in the generation of the ALS phenotype. Two proteins, lysyl-tRNA synthetase and translocon-ass ociated protein delta, interact with mutant forms of SOD1 but not with wild-type SOD1. The specificity of the interactions was confirmed by the coimmunoprecipitation of mutant SOD1 and the expressed proteins. T hese proteins are expressed in ventral cord, lending support to the re levance of this interaction to motor neuron disease.