title: Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins.
abstract: The pathological hallmark of Parkinson's disease is the presence of intracellular inclusions, Lewy bodies, and Lewy neurites, in the dopaminergic neurons of the substantia nigra and several other brain regions. Filamentous alpha-synuclein is the major component of these deposits and its aggregation is believed to play an important role in Parkinson's disease and several other neurodegenerative diseases. Two homologous proteins, beta- and gamma-synucleins, are also abundant in the brain. The synucleins are natively unfolded proteins. beta-Synuclein, which lacks 11 central hydrophobic residues compared with its homologs, exhibited the properties of a random coil, whereas alpha- and gamma-synucleins were slightly more compact and structured. gamma-Synuclein, unlike its homologs, formed a soluble oligomer at relatively low concentrations, which appears to be an off-fibrillation pathway species. Here we show that, although they have similar biophysical properties to alpha-synuclein, beta- And gamma-synucleins inhibit alpha-synuclein fibril formation. Complete inhibition of alpha-synuclein fibrillation was observed at 4:1 molar excess of beta- and gamma-synucleins. No significant incorporation of beta-synuclein into the fibrils was detected. The lack of fibrils formed by beta-synuclein is most readily explained by the absence of a stretch of hydrophobic residues from the middle region of the protein. A model for the inhibition is proposed.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. enzyme@cats.ucsc.edu
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Pierre
authors.initials: P
authors.lastname: Souillac
authors.forename: Ian S
authors.initials: IS
authors.lastname: Millett
authors.forename: Sebastian
authors.initials: S
authors.lastname: Doniach
authors.forename: Ross
authors.initials: R
authors.lastname: Jakes
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Fink
mesh_terms: D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D012542:Scattering, Radiation; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D051843:Synucleins; D013997:Time Factors; D014466:Ultraviolet Rays; D014965:X-Rays; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein