Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases.
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.
de Pril
Remko
R
Research Team Molecular Misreading, Netherlands Institute for Brain Research, Amsterdam, The Netherlands.
Fischer
David F
DF
Maat-Schieman
Marion L C
ML
Hobo
Barbara
B
de Vos
Rob A I
RA
Brunt
Ewout R
ER
Hol
Elly M
EM
Roos
Raymund A C
RA
van Leeuwen
Fred W
FW
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*
D018076:DNA, Complementary; D010455:Peptides; D025801:Ubiquitin; C097188:polyglutamine