Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature

Hum Mol Genet. 2003 Nov 1;12(21):2753-64. doi: 10.1093/hmg/ddg312. Epub 2003 Sep 9.

Abstract

Cu/Zn superoxide dismutase (SOD1), a crucial cellular antioxidant, can in certain settings mediate toxic chemistry through its Cu cofactor. Whether this latter property explains why mutations in SOD1 cause FALS has been debated. Here, we demonstrate motor neuron disease in transgenic mice expressing a SOD1 variant that mutates the four histidine residues that coordinately bind Cu. In-depth analyses of this new mouse model, previously characterized models and FALS human tissues revealed that the accumulation of detergent-insoluble forms of SOD1 is a common feature of the disease. These insoluble species include full-length SOD1 proteins, peptide fragments, stable oligomers and ubiquitinated entities. Moreover, chaperones Hsp25 and alphaB-crystallin specifically co-fractionated with insoluble SOD1. In cultured cells, all 11 of the FALS variants tested produced insoluble forms of mutant SOD1. Importantly, expression of recombinant peptide fragments of wild-type SOD1 in cultured cells also produced insoluble species, suggesting that SOD1 possesses elements with an intrinsic propensity to aggregate. Thus, modifications to the protein, such as FALS mutations, fragmentation and possibly covalent modification, may simply act to augment a natural, but potentially toxic, propensity to aggregate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Axons / metabolism
  • Binding Sites
  • Cells, Cultured
  • Copper / metabolism*
  • Histidine / genetics*
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • alpha-Crystallin B Chain

Substances

  • CRYAB protein, human
  • Intermediate Filament Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • SOD1 protein, human
  • alpha-Crystallin B Chain
  • Histidine
  • Copper
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Protein Kinases
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases