[Neurodegenerative diseases regulated by ubiquitin-proteasome system].
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). E4 B/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 E 4B and MJD1 Ataxin-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.
Hatakeyama
Shigetsugu
S
Department of Molecular Biochemistry, Hokkaido University Graduate School of Medicine.
D000818:Animals; D004330:Drosophila / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex