Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongro-gu, Seoul, 03080, Republic of Korea.
German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
Mol Brain. 2022 Mar 28;15(1):27. doi: 10.1186/s13041-022-00913-y.
Abnormal deposition of α-synuclein aggregates in Lewy bodies and Lewy neurites is the hallmark lesion in Parkinson's disease (PD). These aggregates, thought to be the culprit of disease pathogenesis, spread throughout the brain as the disease progresses. Agents that inhibit α-synuclein aggregation and/or spread of aggregates would thus be candidate disease-modifying drugs. Here, we found that Chicago sky blue 6B (CSB) may be such a drug, showing that it inhibits α-synuclein aggregation and cell-to-cell propagation in both in vitro and in vivo models of synucleinopathy. CSB inhibited the fibrillation of α-synuclein in a concentration-dependent manner through direct binding to the N-terminus of α-synuclein. Furthermore, both seeded polymerization and cell-to-cell propagation of α-synuclein were inhibited by CSB treatment. Notably, CSB alleviated behavioral deficits and neuropathological features, such as phospho-α-synuclein and astrogliosis, in A53T α-synuclein transgenic mice. These results indicate that CSB directly binds α-synuclein and inhibits its aggregation, thereby blocking α-synuclein cell-to-cell propagation.
α-突触核蛋白聚集物在路易体和路易神经突中的异常沉积是帕金森病（PD）的标志性病变。这些聚集物被认为是疾病发病机制的罪魁祸首，随着疾病的进展会在大脑中扩散。因此，抑制α-突触核蛋白聚集和/或聚集物扩散的药物将是候选的疾病修饰药物。在这里，我们发现芝加哥天蓝 6B（CSB）可能就是这样一种药物，它在突触核蛋白病的体外和体内模型中显示出抑制α-突触核蛋白聚集和细胞间传播的作用。CSB 通过直接结合α-突触核蛋白的 N 端以浓度依赖的方式抑制α-突触核蛋白的纤维形成。此外，CSB 处理还抑制了α-突触核蛋白的种子聚合和细胞间传播。值得注意的是，CSB 缓解了 A53T α-突触核蛋白转基因小鼠的行为缺陷和神经病理学特征，如磷酸化α-突触核蛋白和星形胶质细胞增生。这些结果表明 CSB 直接结合α-突触核蛋白并抑制其聚集，从而阻断α-突触核蛋白的细胞间传播。
