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Human Molecular Genetics Advance Access originally published online on June 15, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 16 1803-1813
DOI: 10.1093/hmg/ddh188
Human Molecular Genetics, Vol. 13, No. 16 © Oxford University Press 2004; all rights reserved

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

Remko de Pril1, David F. Fischer1, Marion L.C. Maat-Schieman2, Barbara Hobo1, Rob A.I. de Vos3, Ewout R. Brunt4, Elly M. Hol1, Raymund A.C. Roos2 and Fred W. van Leeuwen1,*

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

Received May 6, 2004; Accepted June 8, 2004

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.

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


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