Small Molecule Inhibitors of α-Synuclein Filament Assembly

• Published in: Biochemistry (Easton) 2006-05, Vol.45 (19), p.6085-6094
• Main Authors: Masuda, Masami, Suzuki, Nobuyuki, Taniguchi, Sayuri, Oikawa, Takayuki, Nonaka, Takashi, Iwatsubo, Takeshi, Hisanaga, Shin-ichi, Goedert, Michel, Hasegawa, Masato
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - antagonists & inhibitors; Cell Line; Chromatography, High Pressure Liquid; Dopamine - metabolism; Electrophoresis, Polyacrylamide Gel; Humans; Neuroblastoma - metabolism; Neuroblastoma - pathology
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi0600749

α-Synuclein is the major component of the filamentous inclusions that constitute defining characteristics of Parkinson's disease and other α-synucleinopathies. Here we have tested 79 compounds belonging to 12 different chemical classes for their ability to inhibit the assembly of α-synuclein into filaments in vitro. Several polyphenols, phenothiazines, porphyrins, polyene macrolides, and Congo red and its derivatives, BSB and FSB, inhibited α-synuclein filament assembly with IC50 values in the low micromolar range. Many compounds that inhibited α-synuclein assembly were also found to inhibit the formation of Aβ and tau filaments. Biochemical analysis revealed the formation of soluble oligomeric α-synuclein in the presence of inhibitory compounds, suggesting that this may be the mechanism by which filament formation is inhibited. Unlike α-synuclein filaments and protofibrils, these soluble oligomeric species did not reduce the viability of SH-SY5Y cells. These findings suggest that the soluble oligomers formed in the presence of inhibitory compounds may not be toxic to nerve cells and that these compounds may therefore have therapeutic potential for α-synucleinopathies and other brain amyloidoses.