Abstract |
Insoluble aggregates of polyglutamine-containing proteins are usually conjugated with ubiquitin in neurons of individuals with polyglutamine diseases. We now show that ataxin-3, in which the abnormal expansion of a polyglutamine tract is responsible for spinocerebellar ataxia type 3 (SCA3), undergoes ubiquitylation and degradation by the proteasome. Mammalian E4B (UFD2a), a ubiquitin chain assembly factor (E4), copurified with the polyubiquitylation activity for ataxin-3. E4B interacted with, and thereby mediated polyubiquitylation of, ataxin-3. Expression of E4B promoted degradation of a pathological form of ataxin-3. In contrast, a dominant-negative mutant of E4B inhibited degradation of this form of ataxin-3, resulting in the formation of intracellular aggregates. In a Drosophila model of SCA3, expression of E4B suppressed the neurodegeneration induced by an ataxin-3 mutant. These observations suggest that E4 is a rate-limiting factor in the degradation of pathological forms of ataxin-3, and that targeted expression of E4B is a potential gene therapy for SCA3.
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Authors | Masaki Matsumoto, Masayoshi Yada, Shigetsugu Hatakeyama, Hiroshi Ishimoto, Teiichi Tanimura, Shoji Tsuji, Akira Kakizuka, Masatoshi Kitagawa, Keiichi I Nakayama |
Journal | The EMBO journal
(EMBO J)
Vol. 23
Issue 3
Pg. 659-69
(Feb 11 2004)
ISSN: 0261-4189 [Print] England |
PMID | 14749733
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Nerve Tissue Proteins
- Nuclear Proteins
- Repressor Proteins
- Transcription Factors
- Ubiquitin
- Ube4b protein, mouse
- Ubiquitin-Protein Ligases
- ATXN3 protein, human
- Ataxin-3
- Atxn3 protein, mouse
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Topics |
- Animals
- Animals, Genetically Modified
- Ataxin-3
- Cell Line
- Cerebellar Ataxia
(genetics, metabolism)
- Drosophila melanogaster
- Humans
- Mice
- Nerve Tissue Proteins
(genetics, metabolism)
- Nuclear Proteins
- Repressor Proteins
- Transcription Factors
- Ubiquitin
(metabolism)
- Ubiquitin-Protein Ligases
(genetics, metabolism)
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