Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death1

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Abstract
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.
Funding Information
  • Human Frontier Science Program (RG0148/1999B)
  • Koninklijke Nederlandse Akademie van Wetenschappen (GPD-NWO 970-10-029)
  • Hersenstichting (H00.06)