title: Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases.
abstract: Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.
authors.affiliation: Research Team Molecular Misreading, Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
authors.forename: Remko
authors.initials: R
authors.lastname: de Pril
authors.forename: David F
authors.initials: DF
authors.lastname: Fischer
authors.forename: Marion L C
authors.initials: ML
authors.lastname: Maat-Schieman
authors.forename: Barbara
authors.initials: B
authors.lastname: Hobo
authors.forename: Rob A I
authors.initials: RA
authors.lastname: de Vos
authors.forename: Ewout R
authors.initials: ER
authors.lastname: Brunt
authors.forename: Elly M
authors.initials: EM
authors.lastname: Hol
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020271:Heredodegenerative Disorders, Nervous System / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D010455:Peptides; D025801:Ubiquitin; C097188:polyglutamine