Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions

Nat Genet. 1997 Jan;15(1):91-4. doi: 10.1038/ng0197-91.


A subset of familial and sporadic amyotrophic lateral sclerosis (ALS-a fatal disorder characterised by progressive motor neuron degeneration) cases are due to mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1). Two mutations which have been successfully used to generate transgenic mice that develop an ALS-like syndrome are glycine 85 to arginine (G85R) and glycine 93 to alanine (G93A) with the mutant SOD1 allele overexpressed in a normal mouse genetic background. No ALS-like phenotype is observed in mice overexpressing wild-type SOD1 or mice without any SOD1 activity. These dominant mutations, which do not necessarily decrease SOD1 activity, may confer a gain of function that is selectively lethal to motor neurons. The yeast interaction trap system allowed us to determine whether these mutations in SOD1 caused novel protein interactions not observed with wild-type SOD1 and which might participate in the generation of the ALS phenotype. Two proteins, lysyl-tRNA synthetase and translocon-associated 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. These proteins are expressed in ventral cord, lending support to the relevance of this interaction to motor neuron disease.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 12E7 Antigen
  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Antigens, CD / metabolism
  • Brain / embryology
  • Brain / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cell Adhesion Molecules / metabolism
  • Escherichia coli
  • Humans
  • Lysine-tRNA Ligase / metabolism
  • Membrane Glycoproteins*
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Protein Binding
  • Proteins / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Peptide / metabolism
  • Recombinant Fusion Proteins / genetics
  • Saccharomyces cerevisiae
  • Spinal Cord / embryology
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism*


  • 12E7 Antigen
  • Antigens, CD
  • CD99 protein, human
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • Membrane Glycoproteins
  • Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Peptide
  • Recombinant Fusion Proteins
  • signal sequence receptor
  • Superoxide Dismutase
  • Lysine-tRNA Ligase

Associated data

  • GENBANK/D31890
  • GENBANK/M16279
  • GENBANK/N22302
  • GENBANK/X90583