title: Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism.
abstract: Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD.
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Ching-Chi
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tu-Hsueh
authors.initials: TH
authors.lastname: Yeh
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Szu-Chia
authors.initials: SC
authors.lastname: Lai
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Yin-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.
authors.forename: Chao-Lang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Chang
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: hlwns@mail.cgu.edu.tw.
authors.forename: Hung-Li
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Neuroscience Research Center, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan; Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: c81214@adm.cgmh.org.tw.
authors.forename: Chin-Song
authors.initials: CS
authors.lastname: Lu
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D020267:MPTP Poisoning / Q000201:enzymology* / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020734:Parkinsonian Disorders; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: D001549:Benzamides; D052117:Benzodioxoles; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D000444:Aldehyde Dehydrogenase
keywords: Alda-1; Aldehyde dehydrogenase 2 (ALDH2); Mitochondrial dysfunction; Parkinson's disease; Rotenone; Substantia nigra dopaminergic neurons