title: Determinants of buildup of the toxic dopamine metabolite DOPAL in Parkinson's disease.
abstract: Intra-neuronal metabolism of dopamine (DA) begins with production of 3,4-dihydroxyphenylacetaldehyde (DOPAL),which is toxic. According to the 'catecholaldehyde hypothesis', DOPAL destroys nigrostriatal DA terminals and contributes to the profound putamen DA deficiency that characterizes Parkinson’s disease (PD). We tested the feasibility of using post-mortem patterns of putamen tissue catechols to examine contributions of altered activities of the type 2 vesicular monoamine transporter (VMAT2) and aldehyde dehydrogenase(ALDH) to the increased DOPAL levels found in PD. Theoretically, the DA : DOPA concentration ratio indicates vesicular uptake, and the 3,4-dihydroxyphenylacetic acid: DOPAL ratio indicates ALDH activity. We validated these indices in transgenic mice with very low vesicular uptake VMAT2-Lo) or with knockouts of the genes encoding ALDH1A1 and ALDH2 (ALDH1A1,2 KO), applied these indices in PD putamen, and estimated the percent decreases in vesicular uptake and ALDH activity in PD. VMAT2-Lo mice had markedly decreased DA:DOPA (50 vs. 1377, p < 0.0001),and ALDH1A1,2 KO mice had decreased 3,4-dihydroxyphenylacetic acid:DOPAL (1.0 vs. 11.2, p < 0.0001). In PD putamen, vesicular uptake was estimated to be decreased by 89% and ALDH activity by 70%. Elevated DOPAL levels in PD putamen reflect a combination of decreased vesicular uptake of cytosolic DA and decreased DOPAL detoxification by ALDH.
authors.affiliation: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1620, USA. goldsteind@ninds.nih.gov
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Patti
authors.initials: P
authors.lastname: Sullivan
authors.forename: Courtney
authors.initials: C
authors.lastname: Holmes
authors.forename: Gary W
authors.initials: GW
authors.lastname: Miller
authors.forename: Shawn
authors.initials: S
authors.lastname: Alter
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kopin
authors.forename: Yehonatan
authors.initials: Y
authors.lastname: Sharabi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001923:Brain Chemistry; D002396:Catechols / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000378:metabolism*; D011699:Putamen / Q000378:metabolism; D050697:Retinal Dehydrogenase; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism / Q000502:physiology
chemical_list: D002396:Catechols; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D004295:Dihydroxyphenylalanine; D000080924:Aldehyde Dehydrogenase 1 Family; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D004298:Dopamine
keywords: DOPAC; DOPAL; DOPET; Parkinson's disease; dopamine; monoamine oxidase