title: Rifampicin inhibits alpha-synuclein fibrillation and disaggregates fibrils.
abstract: The aggregation of alpha-synuclein in dopaminergic neurons of the substantia nigra is a critical step in the pathogenesis of Parkinson's disease. We show that the antibiotic rifampicin inhibited alpha-synuclein fibrillation and disaggregated existing fibrils in a concentration-dependent manner. Size-exclusion chromatography data indicated that rifampicin stabilized alpha-synuclein as both a monomer and soluble oligomers comprised of partially folded alpha-synuclein. Experiments using aged samples of rifampicin indicated that the most active species in inhibiting fibrillation and disaggregating fibrils is an oxidation product of rifampicin, which was confirmed in experiments under anaerobic conditions. These results indicate that rifampicin-mediated inhibition of alpha-synuclein fibrillation and disaggregation of fibrils involves preferential stabilization of monomeric and soluble oligomeric forms, and that rifampicin potentially may have therapeutic application for Parkinson's disease.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Sudha
authors.initials: S
authors.lastname: Rajamani
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D019999:Pharmaceutical Solutions / Q000737:chemistry; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology*; D051843:Synucleins; D014867:Water / Q000737:chemistry; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D019999:Pharmaceutical Solutions; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D014867:Water; D012293:Rifampin