Small molecule inhibitors of α-synuclein filament assembly
Small molecule inhibitors of α-synuclein filament assembly
复制标题
DOI：
10.1021/bi0600749
复制
发表时间：
2006-05-16
期刊：
影响因子：
2.9
通讯作者：
Hasegawa, Masato
中科院分区：
文献类型：
--
作者：
Masuda, Masami;Suzuki, Nobuyuki;Hasegawa, Masato
-突触核蛋白是构成帕金森病和其他-突触核蛋白病定义特征的丝状包涵体的主要成分。在这里，我们测试了属于12种不同化学类别的79种化合物在体外抑制α -突触核蛋白组装成细丝的能力。几种多酚类、吩噻嗪类、卟啉类、多烯大环内酯类和刚果红及其衍生物BSB和FSB抑制α -突触核蛋白丝的组装，IC50值在低微摩尔范围内。许多抑制α -突触核蛋白组装的化合物也被发现能抑制ass和tau细丝的形成。生化分析显示，在抑制化合物存在的情况下，可溶性寡聚α -突触核蛋白的形成，表明这可能是抑制丝形成的机制。与α -突触核蛋白细丝和原原纤维不同，这些可溶性低聚物不会降低SH-SY5Y细胞的活力。这些发现表明，在抑制化合物存在下形成的可溶性低聚物可能对神经细胞没有毒性，因此这些化合物可能具有治疗α -突触核蛋白病和其他脑淀粉样病变的潜力。
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 IC50 values in the low micromolar range. Many compounds that inhibited alpha-synuclein assembly were also found to inhibit the formation of A ss 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.