Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity

Jun Ichi Niwa, Shinsuke Ishigaki, Nozomi Hishikawa, Masahiko Yamamoto, Manabu Doyu, Shigeo Murata, Keiji Tanaka, Naoyuki Taniguchi, Gen Sobue

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord. The cytopathological hallmark in the remaining motor neurons of ALS is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. In this paper we report that Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well as sporadic ALS. Dorfin physically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation, but it had no effect on the stability of the wild-type SOD1. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions. Our results indicate that Dorfin protects neurons by recognizing and then ubiquitylating mutant SOD1 proteins followed by targeting them for proteasomal degradation.

Original languageEnglish
Pages (from-to)36793-36798
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number39
DOIs
Publication statusPublished - Sep 27 2002
Externally publishedYes

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Neurons
Amyotrophic Lateral Sclerosis
Motor Neurons
Degradation
Ubiquitin-Protein Ligases
Poisons
Inclusion Bodies
Protein Transport
Mutant Proteins
Cerebral Cortex
Brain Stem
Superoxide Dismutase
Zinc
Copper
Spinal Cord
Mutation
Amyotrophic lateral sclerosis 1
Proteins
Protein Aggregates
Superoxide Dismutase-1

ASJC Scopus subject areas

  • Biochemistry

Cite this

Niwa, J. I., Ishigaki, S., Hishikawa, N., Yamamoto, M., Doyu, M., Murata, S., ... Sobue, G. (2002). Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. Journal of Biological Chemistry, 277(39), 36793-36798. https://doi.org/10.1074/jbc.M206559200

Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. / Niwa, Jun Ichi; Ishigaki, Shinsuke; Hishikawa, Nozomi; Yamamoto, Masahiko; Doyu, Manabu; Murata, Shigeo; Tanaka, Keiji; Taniguchi, Naoyuki; Sobue, Gen.

In: Journal of Biological Chemistry, Vol. 277, No. 39, 27.09.2002, p. 36793-36798.

Research output: Contribution to journalArticle

Niwa, JI, Ishigaki, S, Hishikawa, N, Yamamoto, M, Doyu, M, Murata, S, Tanaka, K, Taniguchi, N & Sobue, G 2002, 'Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity', Journal of Biological Chemistry, vol. 277, no. 39, pp. 36793-36798. https://doi.org/10.1074/jbc.M206559200
Niwa, Jun Ichi ; Ishigaki, Shinsuke ; Hishikawa, Nozomi ; Yamamoto, Masahiko ; Doyu, Manabu ; Murata, Shigeo ; Tanaka, Keiji ; Taniguchi, Naoyuki ; Sobue, Gen. / Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 39. pp. 36793-36798.
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AB - Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the cerebral cortex, brainstem, and spinal cord. The cytopathological hallmark in the remaining motor neurons of ALS is the presence of ubiquitylated inclusions consisting of insoluble protein aggregates. In this paper we report that Dorfin, a RING finger-type E3 ubiquitin ligase, is predominantly localized in the inclusion bodies of familial ALS with a copper/zinc superoxide dismutase (SOD1) mutation as well as sporadic ALS. Dorfin physically bound and ubiquitylated various SOD1 mutants derived from familial ALS patients and enhanced their degradation, but it had no effect on the stability of the wild-type SOD1. The overexpression of Dorfin protected against the toxic effects of mutant SOD1 on neural cells and reduced SOD1 inclusions. Our results indicate that Dorfin protects neurons by recognizing and then ubiquitylating mutant SOD1 proteins followed by targeting them for proteasomal degradation.

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