title: The serotonin aldehyde, 5-HIAL, oligomerizes alpha-synuclein.
abstract: In Parkinson's disease (PD) alpha-synuclein oligomers are thought to be pathogenic, and 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate aldehyde intermediate in neuronal dopamine metabolism, potently oligomerizes alpha-synuclein. PD involves alpha-synuclein deposition in brainstem raphe nuclei; however, whether 5-hydroxyindoleacetaldehyde (5-HIAL), the aldehyde of serotonin, oligomerizes alpha-synuclein has been unknown. In this study we tested whether 5-HIAL oligomerizes alpha-synuclein in vitro and in PC12 cells conditionally over-expressing alpha-synuclein. Alpha-synuclein oligomers were quantified by western blotting after incubation of alpha-synuclein with serotonin and monoamine oxidase-A (MAO-A) to generate 5-HIAL or dopamine to generate DOPAL. Oligomerization of alpha-synuclein in PC12 cells over-expressing the protein was compared between vehicle-treated cells and cells incubated with levodopa to generate DOPAL or 5-hydroxytryptophan to generate 5-HIAL. Monoamine aldehyde mediation of the oligomerization was assessed using the MAO inhibitor, pargyline. Dopamine and serotonin incubated with MAO-A both strongly oligomerized alpha-synuclein (more than 10 times control); pargyline blocked the oligomerization. In synuclein overexpressing PC12 cells, levodopa and 5-hydroxytryptophan elicited pargyline-sensitive alpha-synuclein oligomerization. 5-HIAL oligomerizes alpha-synuclein both in vitro and in synuclein-overexpressing PC12 cells, in a manner similar to DOPAL. The findings may help explain loss of serotonergic neurons in PD.
authors: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA.
authors: Yunden
authors: Y
authors: Jinsmaa
authors: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA.
authors: Adele
authors: A
authors: Cooney
authors: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA.
authors: Patricia
authors: P
authors: Sullivan
authors: Department of Internal Medicine, Chaim Sheba Medical Center, Tel-HaShomer, Israel.
authors: Yehonatan
authors: Y
authors: Sharabi
authors: Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892 USA. Electronic address: goldsteind@ninds.nih.gov.
authors: David S
authors: DS
authors: Goldstein
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016716:PC12 Cells; D010293:Pargyline / Q000494:pharmacology; D058105:Polymerization; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; C004277:hydroxyindoleacetaldehyde; D012701:Serotonin; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D010293:Pargyline; D006916:5-Hydroxytryptophan; D008995:Monoamine Oxidase; D004298:Dopamine
keywords: 3,4-Dihydroxyphenylacetaldehyde; 5-Hydroxyindolealdehyde; Dopamine; Parkinson’ disease; Serotonin
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