title: Engineered alpha-synuclein prevents wild type and familial Parkin variant fibril formation.
abstract: Alpha-synuclein is a major component of several pathological lesions diagnostic of specific neurodegenerative disease such as Parkinson's disease. This study focuses on the non-amyloid beta component of Alzheimer's disease amyloid, a key region for the aggregation and fibril formation of alpha-synuclein. Several mutations were introduced in an attempt to repress beta-strand formation and hydrophobic interaction-based aggregation. Although reducing the hydrophobicity drastically decreased fibril formation, the Val70Thr and Val70Pro mutations resulted in an unstable secondary structure thereby increasing non-structural aggregation, instead of fibril formation. Therefore, the stabilization of non-structural natively unfolded status is important to prevent alpha-synuclein fibril formation. Mixing the Val70Thr/Val71Thr double mutant, which has inherently low potential, with the fibril forming alpha-synucleins, WT and Ala53Thr, greatly reduced their fibril formation and aggregation. This double mutant has great potential for further therapeutic approaches.
authors.affiliation: Department of Biotechnology, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, 184-8588 Tokyo, Koganei, Japan. sode@cc.tuat.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Sode
authors.forename: Eri
authors.initials: E
authors.lastname: Usuzaka
authors.forename: Natsuki
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ochiai
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D008027:Light; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D012542:Scattering, Radiation; D051843:Synucleins; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics; D014466:Ultraviolet Rays; D014633:Valine / Q000737:chemistry; D051844:alpha-Synuclein
chemical_list: D000682:Amyloid; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D010455:Peptides; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D004247:DNA; D011392:Proline; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D014633:Valine