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• Vol.46 No.11
• CLINICA NEUROL, 46: 890−892, 2006
• Vol.46 No.11 contents

The 47th Annual Meeting of the Japanese Society of Neurology

Neurodegenerative diseases regulated by ubiquitin-proteasome system

Shigetsugu Hatakeyama, M.D., Ph. D.

Department of Molecular Biochemistry, Hokkaido University Graduate School of Medicine

Various inherited neurodegenerative diseases result from an increase in the number of glutamine codon repeats within the open reading frame of the responsible gene. Insoluble aggregates of polyglutamine-containing proteins in neurons, which are usually conjugated with ubiquitin, are a hallmark of the polyglutamine diseases. However, the molecular mechanism underlying the ubiquitylation and aggregate formation of polyglutamine-containing proteins has been largely unclear. Here we report the identification of critical factors involved in the ubiquitylation process as well as turnover of MJD1/Ataxin-3 protein, in which the abnormal expansion of a polyglutamine tract is responsible for spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease). E4B/UFD2a (a ubiquitin chain assembly factor) and VCP (a AAA-family ATPase) were co-purified with the activity polyubiquitylating Ataxin-3. E4B mediated polyubiquitylation of MJD1/Ataxin-3, and VCP interacted with both E4B and MJD1Ataxin-3. 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 proteins with expanded polyglutamine tracts.

(CLINICA NEUROL, 46: 890−892, 2006)
key words: ubiquitin, U-box, CHIP, UFD2, MJD1/Ataxin-3

(Received: 12-May-06)