title: Observation of multiple intermediates in alpha-synuclein fibril formation by singular value decomposition analysis.
abstract: One of the most well known characteristics for Parkinson's disease (PD) is a polymerization of wild-type or mutant alpha-synuclein into aggregates and fibrils, commonly observed as Lewy bodies and Lewy neuritis in PD patients. Although numerous studies on alpha-synuclein fibrillation have been reported, the molecular mechanisms of aggregation and fibrillation are not well understood yet. In the present study, structural properties and propensities to form fibrils of wild-type, A30P, E46K, and A53T alpha-synucleins were investigated using fluorescence and circular dichroism (CD) methods. The results from these studies were analyzed using singular value decomposition (SVD) method which estimates a number of conformationally independent species for a given process. The time-dependent CD spectra of the wild-type alpha-synuclein indicated a multi-step process in the fibril formation, and SVD analysis using the time-dependent CD spectra revealed that five or nine intermediates were formed at the early stage of fibrillation.
authors.affiliation: School of Life Science, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo 192-0392, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kamiyoshihara
authors.forename: Masaki
authors.initials: M
authors.lastname: Kojima
authors.forename: Kenji
authors.initials: K
authors.lastname: Uéda
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Tashiro
authors.forename: Sakurako
authors.initials: S
authors.lastname: Shimotakahara
mesh_terms: D002942:Circular Dichroism; D006801:Humans; D010300:Parkinson Disease / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein