Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death

• Published in: The FASEB journal Vol. 15; no. 14; p. 2680
• Main Authors: De Vrij, F M, Sluijs, J A, Gregori, L, Fischer, D F, Hermens, W T, Goldgaber, D, Verhaagen, J, Van Leeuwen, F W, Hol, E M
• Format: Journal Article
• Language: English
• Published: United States 01.12.2001
• Subjects: Adenosine Triphosphate - pharmacology; Adenoviridae - genetics; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Apoptosis - physiology; Blotting, Western; Cell Nucleus - metabolism; Cysteine Endopeptidases - drug effects; Cysteine Endopeptidases - metabolism; Genetic Vectors - genetics; Humans; Lac Operon - genetics; Multienzyme Complexes - drug effects; Multienzyme Complexes - metabolism; Mutation; Neurons - cytology; Neurons - metabolism; Proteasome Endopeptidase Complex; Proteins - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Signal Transduction - drug effects; Tumor Cells, Cultured; Ubiquitin - drug effects; Ubiquitin - genetics; Ubiquitin - metabolism
• ISSN: 1530-6860
• DOI: 10.1096/fj.01-0438com

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.