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Human Molecular Genetics Advance Access published online on June 15, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh188
© 2004 by Oxford University Press
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Article

Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases

Remko de Pril 1, David F. Fischer 1, Marion L.C. Maat-Schieman 2, Barbara Hobo 1, Rob A.I. de Vos 3, Ewout R. Brunt 4, Elly M. Hol 1, Raymund A.C. Roos 2, Fred W. van Leeuwen 1*

1 Research Team Molecular Misreading, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
2 Department of Neurology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
3 Laboratory of Pathology East Netherlands, 7512 AD Enschede, The Netherlands
4 Department of Neurology, University Hospital Groningen, 9713 AW Groningen, The Netherlands

* To whom correspondence should be addressed. E-mail: f.van.leeuwen{at}nih.knaw.nl.


  Abstract

Polyglutamine diseases are characterized by neuronal intranuclear inclusions of expanded polyglutamine proteins, indicating failing 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 neuronal intranuclear inclusions 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.


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