Proteasomal dysfunction induced by 4-hydroxy-2,3-trans-nonenal, an end-product of lipid peroxidation: a mechanism contributing to neurodegeneration?
4-Hydroxy-2,3-trans-nonenal (HNE) is a neurotoxic unsaturated aldehyde end-product of lipid peroxidation. The addition of HNE to NT-2 and SK-N-MC cell lines induces apoptosis and we now investigated the time-course of events occurring prior to apoptosis. Treatment of both NT-2 and SK-N-MC cell lines with HNE led to HNE association with the proteasome, increased levels of protein carbonyls and ubiquitinated proteins, and decreased proteasomal function. There was also decreased metabolic activity, cytochrome c release and activation of caspase 3, followed by apoptotic changes including chromatin condensation, cell shrinkage and DNA fragmentation and laddering. Overexpression of mutant superoxide dismutase 1 proteins associated with amyotrophic lateral sclerosis decreased proteasomal activities in the absence of HNE and accelerated the apoptosis induced by HNE. By contrast, overexpression of wild-type superoxide dismutase 1 did not affect basal levels of proteasomal activity. The data suggest that accumulation of ubiquitinated proteins and impairment of proteasomal function are important events in HNE toxicity. We propose that the proteasomal system is a significant target of HNE neurotoxicity in a wide range of neurodegenerative diseases, especially if abnormal proteins are being expressed.
Hyun
Dong-Hoon
DH
Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College, London, UK.
Lee
Moon-Hee
MH
Halliwell
Barry
B
Jenner
Peter
P
D000447:Aldehydes / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D003574:Cytochrome c Group / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D018243:Teratocarcinoma / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D009097:Multienzyme Complexes; D025801:Ubiquitin; D013482:Superoxide Dismutase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal