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Graduate School for Neurosciences Amsterdam, Netherlands Institute for Brain Research, Research Group Molecular Misreading, Amsterdam, The Netherlands;
* Molecular Neurovirology Unit, Veterans Affairs Research Service, Baltimore, Maryland, USA; and
Department of Psychiatry and Behavioral Science, School of Medicine, State University of New York, Stony Brook, New York, USA
1Correspondence: Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. E-mail: e.hol{at}nih.knaw.nl
Ubiquitin-B+1 (UBB+1) is a mutant ubiquitin that accumulates in the neurones of patients with Alzheimer’s disease (AD). Here we report on the biochemical and functional differences between ubiquitin and UBB+1 and the effect of the mutant protein on neuronal cells. UBB+1 lacks the capacity to ubiquitinate, and although it is ubiquitinated itself, UBB+1 is not degraded by the ubiquitin-proteasomal system and is quite stable in neuronal cells. Overexpression of UBB+1 in neuroblastoma cells significantly induces nuclear fragmentation and cell death. Our results demonstrate that accumulation of UBB+1 in neurones is detrimental and may contribute to neuronal dysfunction in AD patients.—de Vrij, F. M. S., Sluijs, J. A., Gregori, L., Fischer, D. F., Hermens, W. T. J. M. C., Goldgaber, D., Verhaagen, J., van Leeuwen, F. W., Hol, E. M. Mutant ubiquitin expressed in Alzheimer’s disease causes neuronal death.
Key Words: AD • molecular misreading • neurodegeneration • proteasomal degradation
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