Effect of the overexpression of mutant ubiquitin (K48R) on the cellular response induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation

Impairment of the ubiquitin-proteasome system (UPS) for degrading abnormal proteins leads to protein aggregates and increased protein oxidation/nitration. This study was performed to show that interference with polyubiquitination in the presence of 4-hydroxy-2,3-trans-nonenal (HNE) has similar consequences. Levels of polyubiquitin chains were not increased in NT-2 and SK-N-MC cells overexpressing a dominant-negative mutant form of ubiquitin (K48R) in response to HNE compared to wild-type transfectants. Increased oxidative (GSH, protein carbonyls and lipid peroxidation) and nitrative damage (nitric oxide production and elevated protein nitration) were aggravated in the mutant transfectants. These data show that initial oxidative/nitrative damage (due to HNE) and interference with ubiquitination (induced by mutant ubiquitin or HNE) can cause common characteristics of neurodegenerative diseases. These data suggest that impairment of the UPS at different levels may be a common mechanism in neurodegeneration and that more such defects remain to be identified.