Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro

• Published in: The Journal of biological chemistry 1999-03, Vol.274 (12), p.7619-7622
• Main Authors: Giasson, B I, Uryu, K, Trojanowski, J Q, Lee, V M
• Format: Article
• Language: English
• Subjects: alpha-Synuclein; Amino Acid Substitution; Cytoskeleton - ultrastructure; Detergents; Humans; Microscopy, Electron; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Parkinson Disease - genetics; Phosphoproteins - genetics; Phosphoproteins - metabolism; Protein Conformation; Sodium Dodecyl Sulfate; Solubility; Synucleins
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.12.7619

alpha-Synuclein is a soluble presynaptic protein which is pathologically redistributed within intracellular lesions characteristic of several neurodegenerative diseases. Here we demonstrate that wild type and two mutant forms of alpha-synuclein linked to familial Parkinson's disease (Ala30 --> Pro and Ala53 --> Thr) self-aggregate and assemble into 10-19-nm-wide filaments with distinct morphologies under defined in vitro conditions. Immunogold labeling demonstrates that the central region of all these filaments are more robustly labeled than the N-terminal or C-terminal regions, suggesting that the latter regions are buried within the filaments. Since in vitro generated alpha-synuclein filaments resemble the major ultrastructural elements of authentic Lewy bodies that are hallmark lesions of Parkinson's disease, we propose that self-aggregating alpha-synuclein is the major subunit protein of these filamentous lesions.