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Interference with ubiquitination causes oxidative damage and increased protein nitration: implications for neurodegenerative diseases
Author(s) -
Hyun DongHoon,
Gray Douglas A.,
Halliwell Barry,
Jenner Peter
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02493.x
Subject(s) - nitration , lipid peroxidation , proteasome , ubiquitin , chemistry , oxidative phosphorylation , oxidative stress , nitric oxide , biochemistry , protein degradation , microbiology and biotechnology , biology , gene , organic chemistry
Inhibition of the proteasomal pathway for degrading abnormal proteins leads to protein aggregation, increased oxidative damage and increased protein nitration. We now show that interference with polyubiquitination has similar consequences. Expression of a dominant‐negative mutant form of ubiquitin (K48R) in NT‐2 and SK‐N‐MC cells caused decreased cell growth rates and increased oxidative damage (protein carbonyls and lipid peroxidation), nitric oxide production and elevated protein nitration. It also rendered cells highly sensitive to 4‐hydroxy‐2,3‐ trans ‐nonenal, a neurotoxic end‐product of lipid peroxidation, hydrogen peroxide and deprivation of growth factors. Overexpression of wild‐type ubiquitin did not produce these effects. Our data show that interference with the ubiquitin‐proteasome pathway at a different point and by a different mechanism can produce many of the common features of human neurodegenerative diseases, such as increased lipid peroxidation, protein oxidation and protein nitration. We suggest that defects in this pathway at multiple points could produce the common features of neurodegenerative diseases, and that more such defects remain to be discovered.