title: Small molecule inhibitors of alpha-synuclein filament assembly.
abstract: Alpha-synuclein is the major component of the filamentous inclusions that constitute defining characteristics of Parkinson's disease and other alpha-synucleinopathies. Here we have tested 79 compounds belonging to 12 different chemical classes for their ability to inhibit the assembly of alpha-synuclein into filaments in vitro. Several polyphenols, phenothiazines, porphyrins, polyene macrolides, and Congo red and its derivatives, BSB and FSB, inhibited alpha-synuclein filament assembly with IC(50) values in the low micromolar range. Many compounds that inhibited alpha-synuclein assembly were also found to inhibit the formation of Abeta and tau filaments. Biochemical analysis revealed the formation of soluble oligomeric alpha-synuclein in the presence of inhibitory compounds, suggesting that this may be the mechanism by which filament formation is inhibited. Unlike alpha-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 alpha-synucleinopathies and other brain amyloidoses.
authors: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
authors: Masami
authors: M
authors: Masuda
authors: Nobuyuki
authors: N
authors: Suzuki
authors: Sayuri
authors: S
authors: Taniguchi
authors: Takayuki
authors: T
authors: Oikawa
authors: Takashi
authors: T
authors: Nonaka
authors: Takeshi
authors: T
authors: Iwatsubo
authors: Shin-ichi
authors: S
authors: Hisanaga
authors: Michel
authors: M
authors: Goedert
authors: Masato
authors: M
authors: Hasegawa