1. Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases
- Author
-
Raymund A.C. Roos, Ewout R. Brunt, Rob A.I. de Vos, Fred W. van Leeuwen, David F. Fischer, Elly M. Hol, Remko de Pril, Barbara Hobo, and Marion L.C. Maat-Schieman
- Subjects
Programmed cell death ,DNA, Complementary ,Cell Survival ,Blotting, Western ,Fluorescent Antibody Technique ,PROTEIN ,Apoptosis ,Protein degradation ,Biology ,Transfection ,Ubiquitin ,EXPANDED POLYGLUTAMINE ,Tumor Cells, Cultured ,Genetics ,medicine ,Humans ,Cloning, Molecular ,GENE-PRODUCT ,Molecular Biology ,Genetics (clinical) ,INTRANUCLEAR INCLUSIONS ,Inclusion Bodies ,Ubiquitin B ,Neurodegeneration ,Brain ,General Medicine ,medicine.disease ,Immunohistochemistry ,Molecular biology ,Cell biology ,ALZHEIMERS-DISEASE ,Proteasome ,Cytoplasm ,CALCIUM-CHANNEL ,HUNTINGTONS-DISEASE ,Spinocerebellar ataxia ,biology.protein ,Heredodegenerative Disorders, Nervous System ,DYSTROPHIC NEURITES ,Peptides ,PROTEASOME SYSTEM ,MUTANT UBIQUITIN ,Plasmids - 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.
- Published
- 2004
- Full Text
- View/download PDF