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NEDL1, a novel ubiquitin-protein isopeptide ligase for dishevelled-1, targets mutant superoxide dismutase-1.

Approximately 20% of familial amyotrophic lateral sclerosis (FALS) arises from germ-line mutations in the superoxide dismutase-1 (SOD1) gene. However, the molecular mechanisms underlying the process have been elusive. Here, we show that a neuronal homologous to E6AP carboxyl terminus (HECT)-type ubiquitin-protein isopeptide ligase (NEDL1) physically binds translocon-associated protein-delta and also binds and ubiquitinates mutant (but not wild-type) SOD1 proportionately to the disease severity caused by that particular mutant. Immunohistochemically, NEDL1 is present in the central region of the Lewy body-like hyaline inclusions in the spinal cord ventral horn motor neurons of both FALS patients and mutant SOD1 transgenic mice. Two-hybrid screening for the physiological targets of NEDL1 has identified Dishevelled-1, one of the key transducers in the Wnt signaling pathway. Mutant SOD1 also interacted with Dishevelled-1 in the presence of NEDL1 and caused its dysfunction. Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-delta, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS.

Pubmed ID: 14684739


  • Miyazaki K
  • Fujita T
  • Ozaki T
  • Kato C
  • Kurose Y
  • Sakamoto M
  • Kato S
  • Goto T
  • Itoyama Y
  • Aoki M
  • Nakagawara A


The Journal of biological chemistry

Publication Data

March 19, 2004

Associated Grants


Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cloning, Molecular
  • DNA Primers
  • Humans
  • Hydrolysis
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Mutation
  • Nerve Tissue Proteins
  • Phosphoproteins
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Superoxide Dismutase
  • Tumor Cells, Cultured
  • Ubiquitin-Protein Ligases