title: Smoking and Parkinson's disease: does nicotine affect alpha-synuclein fibrillation?
abstract: alpha-synuclein is a small presynaptic protein (14,460 D) that is abundantly distributed in the brain. Although, its function is unknown, the aggregated form of alpha-synuclein is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease (PD). Epidemiological studies have shown that smoking can lessen the incidence of Parkinson's disease, indicating that smoke may contain chemicals that are neuro-protective. The fibrillation of alpha-synuclein was studied in relation to five different compounds found in cigarette smoke: anabasine, cotinine, hydroquinone, nicotine and nornicotine. Thioflavin T assays, gel electrophoresis, size exclusion chromatography-high performance liquid chromatography (SEC-HPLC) and atomic force microscopy (AFM) were utilized to monitor the rate of alpha-synuclein fibrillation and the inhibitory effects of the cigarette smoke components. We show that nicotine and hydroquinone inhibit alpha-synuclein fibril formation in a concentration-dependent manner, with nicotine being more effective. The SEC-HPLC data show that nicotine and hydroquinone stabilize soluble oligomers. The morphology of the oligomers stabilized by nicotine was evaluated by AFM, which showed the presence of three stable oligomers with an average height of 16 nm, 10 nm and 4 nm. Comparable results were obtained for the effect of the cigarette smoke components on the A53T mutant fibrillation. These results show that nicotine and hydroquinone inhibit alpha-synuclein fibrillation and stabilize soluble oligomeric forms. This information can be used to understand the molecular mechanism of the nicotine and hydroquinone action to develop therapeutic solutions for PD.
authors.affiliation: Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
authors.forename: Dong-Pyo
authors.initials: DP
authors.lastname: Hong
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D000595:Amino Acid Sequence; D000691:Anabasine / Q000494:pharmacology; D052160:Benzothiazoles; D002850:Chromatography, Gel; D003367:Cotinine / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009154:Mutation; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D012907:Smoking / Q000009:adverse effects*; D013844:Thiazoles / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D052160:Benzothiazoles; D006873:Hydroquinones; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T; D009538:Nicotine; C005311:nornicotine; D003367:Cotinine; D000691:Anabasine; C031927:hydroquinone