title: Modulation of aldehyde dehydrogenase activity affects (±)-4-hydroxy-2E-nonenal (HNE) toxicity and HNE-protein adduct levels in PC12 cells.
abstract: Oxidative stress is known to be one of the major factors underlying Parkinson's disease (PD). One of the consequences of oxidative stress is lipid peroxidation. A toxic product of lipid peroxidation, (±)-4-hydroxy-2E-nonenal (HNE) leads to membrane disruption and formation of HNE-protein adducts and such adducts have been detected in PD brain tissues. Aldehyde dehydrogenases (ALDHs) are involved in metabolizing HNE and other endogenous aldehydes. Interestingly, the cytosolic aldehyde dehydrogenase 1A1 (ALDH1A1) has been reported to be down-regulated in brain tissues affected in PD which could result in enhancement of HNE toxicity. We sought to first establish the role of ALDH1A1 in mediating HNE toxicity in PC12 cells by overexpressing ALDH1A1 and by using disulfiram, an ALDH inhibitor. Overexpression and inhibition of ALDH1A1 activity resulted in reduced and increased HNE toxicity, respectively. We then established conditions for detecting HNE-protein adducts following HNE treatment and showed that overexpression and inhibition of ALDH activity resulted in reduced and increased formation of HNE-protein adducts, respectively. We also show that 6-methyl-2-(phenylazo)-3-pyridinol, previously identified as an activator of ALDH1A1, can protect PC12 cells against HNE-mediated toxicity and can cause a small but significant decrease in levels of HNE-protein adducts. Our results should encourage identification of more potent ALDH activators and their testing in the PC12-HNE model. Such cytoprotective compounds could then be tested for their neuroprotective activity in in vivo models of oxidative stress-induced PD.
authors.affiliation: Exonhit Inc., Gaithersburg, MD 20877, USA.
authors.forename: Dehe
authors.initials: D
authors.lastname: Kong
authors.forename: Vinayaka
authors.initials: V
authors.lastname: Kotraiah
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; C462359:tert-4-hydroxy-2-nonenal; D000080924:Aldehyde Dehydrogenase 1 Family; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase; D004221:Disulfiram