Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1

Takashi Ito, Jun ichi Niwa, Nozomi Hishikawa, Shinsuke Ishigaki, Manabu Doyu, Gen Sobue

Research output: Contribution to journalArticle

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Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of nigra dopaminergic neurons. Lewy bodies (LBs) are a characteristic neuronal inclusion in PD brains. In this study, we report that Dorfin, a RING finger-type ubiquityl ligase for mutant superoxide dismutase-1, was localized with ubiquitin in LBs. Recently, synphilin-1 was identified to associate with α-synuclein and to be a major component of LBs. We found that overexpression of synphilin-1 in cultured cells led to the formation of large juxtanuclear inclusions, but showed no cytotoxicity. Dorfin colocalized in these large inclusions with ubiquitin and proteasomal components. In contrast to full-length synphilin-1, over-expression of the central portion of synphilin-1, including ankyrin-like repeats, a coiled-coil domain, and an ATP/GTP-binding domain, predominantly led to the formation of small punctate aggregates scattered throughout the cytoplasm and showed cytotoxic effects. Dorfin and ubiquitin did not localize in these small aggregates. Overexpression of the N or C terminus of synphilin-1 did not lead to the formation of any aggregates. Dorfin physically bound and ubiquitylated synphilin-1 through its central portion, but did not ubiquitylate wild-type or mutant α-synuclein. These results suggest that the central domain of synphilin-1 has an important role in the formation of aggregates and cytotoxicity and that Dorfin may be involved in the pathogenic process of PD and LB formation by ubiquitylation of synphilin-1.

Original languageEnglish
Pages (from-to)29106-29114
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number31
DOIs
Publication statusPublished - Aug 1 2003
Externally publishedYes

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Lewy Bodies
Ubiquitin
Synucleins
Parkinson Disease
Cytotoxicity
Ankyrin Repeat
Ubiquitination
Dopaminergic Neurons
Neurodegenerative diseases
Ligases
Guanosine Triphosphate
Neurodegenerative Diseases
Cultured Cells
Cytoplasm
Adenosine Triphosphate
Neurons
Superoxide Dismutase
Brain
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. / Ito, Takashi; Niwa, Jun ichi; Hishikawa, Nozomi; Ishigaki, Shinsuke; Doyu, Manabu; Sobue, Gen.

In: Journal of Biological Chemistry, Vol. 278, No. 31, 01.08.2003, p. 29106-29114.

Research output: Contribution to journalArticle

Ito, T, Niwa, JI, Hishikawa, N, Ishigaki, S, Doyu, M & Sobue, G 2003, 'Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1', Journal of Biological Chemistry, vol. 278, no. 31, pp. 29106-29114. https://doi.org/10.1074/jbc.M302763200
Ito, Takashi ; Niwa, Jun ichi ; Hishikawa, Nozomi ; Ishigaki, Shinsuke ; Doyu, Manabu ; Sobue, Gen. / Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 31. pp. 29106-29114.
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