title: Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes.
abstract: The Parkinson's disease substantia nigra is characterized by the loss of dopaminergic neurons and the presence of cytoplasmic fibrillar Lewy bodies in surviving neurons. The major fibrillar protein of Lewy bodies is alpha-synuclein. Two point mutations in the alpha-synuclein gene are associated with autosomal-dominant Parkinson's disease (FPD). Studies of the in vitro fibrillization behavior of the mutant proteins suggest that fibril precursors, or alpha-synuclein protofibrils, rather than the fibrils, may be pathogenic. Atomic force microscopy (AFM) revealed two distinct forms of protofibrillar alpha-synuclein: rapidly formed spherical protofibrils and annular protofibrils, which were produced on prolonged incubation of spheres. The spherical protofibrils bound to brain-derived membrane fractions much more tightly than did monomeric or fibrillar alpha-synuclein, and membrane-associated annular protofibrils were observed. The structural features of alpha-synuclein annular protofibrils are reminiscent of bacterial pore-forming toxins and are consistent with their porelike activity in vitro. Thus, abnormal membrane permeabilization may be a pathogenic mechanism in PD.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Tomas T
authors.initials: TT
authors.lastname: Ding
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.forename: Peter T
authors.initials: PT
authors.lastname: Lansbury
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D018625:Microscopy, Atomic Force; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D010539:Permeability; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D012996:Solutions; D013329:Structure-Activity Relationship; D051843:Synucleins; D013997:Time Factors; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; D011498:Protein Precursors; C497604:SNCA protein, human; C497606:Snca protein, rat; D012996:Solutions; D051843:Synucleins; D051844:alpha-Synuclein