Interference with ubiquitination causes oxidative damage and increased protein nitration: implications for neurodegenerative diseases

Journal of Neurochemistry
D HyunP Jenner

Abstract

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.

Citations

Oct 16, 2007·Journal of Toxicology and Environmental Health. Part a·Wonsuk Yang, Evelyn Tiffany-Castiglioni
Aug 8, 2007·Aging Cell·Vita A VernaceMaria E Figueiredo-Pereira
Jul 25, 2006·European Journal of Pharmacology·D Allan ButterfieldRukhsana Sultana
Sep 28, 2005·Neurochemical Research·V CalabreseE Rizzarelli
Jun 27, 2006·Journal of Cellular and Molecular Medicine·Isabella Dalle-DonneAldo Milzani
Dec 28, 2006·Neurochemical Research·Vittorio CalabreseAnnamaria Giuffrida Stella
Aug 16, 2008·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Russell T HeppleSataro Goto

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