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

Nature Genetics volume 15, pages 9194 (1997) | Download Citation

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Abstract

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)1–4. 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 SOD7 allele overexpressed in a normal mouse genetic background5–7. No ALS-like phenotype is observed in mice overexpressing wild-type SOD1 or mice without any SOD1 activity6,8,9. These dominant mutations, which do not necessarily decrease SOD1 activity, may confer a gain of function that is selectively lethal to motor neurons5,10–12. The yeast interaction trap system13 allowed us to determine whether these mutations in SOD7 caused novel protein interactions not observed with wild-type SOD7 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.

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Affiliations

  1. Eleanor Roosevelt Institute for Cancer Research, and Human Medical Genetics Program and Departments of Biochemistry, Biophysics and Genetics and Medicine of the University of Colorado Health Science Center, 1899 Gaylord Street, Denver, Colorado 80206, USA.

    • Catherine B. Kunst
    •  & David Patterson
  2. laboratory of Cell Biology, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

    • Eva Mezey
    •  & Michael J. Brownstein
  3. (e-mail: davepatt@eri. uchsc.edu).

    • David Patterson

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DOI

https://doi.org/10.1038/ng0197-91

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