Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis

Hideyuki Takeuchi, Jun Ichi Niwa, Nozomi Hishikawa, Shinsuke Ishigaki, Fumiaki Tanaka, Manabu Doyu, Gen Sobue

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19 Citations (Scopus)


Dorfin is a RING-finger type ubiquitin ligase for mutant superoxide dismutase 1 (SOD1) that enhances its degradation. Mutant SOD1s cause familial amyotrophic lateral sclerosis (FALS) through the gain of unelucidated toxic properties. We previously showed that the accumulation of mutant SOD1 in the mitochondria triggered the release of cytochrome c, followed by the activation of the caspase cascade and induction of neuronal cell death. In the present study, therefore, we investigated whether Dorfin can modulate the level of mutant SOD1 in the mitochondria and subsequent caspase activation. We showed that Dorfin significantly reduced the amount of mutant SOD1 in the mitochondria, the release of cytochrome c and the activation of the following caspase cascade, thereby preventing eventual neuronal cell death in a neuronal cell model of FALS. These results suggest that reducing the accumulation of mutant SOD1 in the mitochondria may be a new therapeutic strategy for mutant SOD1-associated FALS, and that Dorfin may play a significant role in this.

Original languageEnglish
Pages (from-to)64-72
Number of pages9
JournalJournal of Neurochemistry
Issue number1
Publication statusPublished - Apr 2004
Externally publishedYes



  • Amyotrophic lateral sclerosis
  • Dorfin
  • Mitochondria
  • Neuronal cell death
  • Superoxide dismutase 1
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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