Department of Biotechnology, Graduate School of Engineering, Tokyo University of Agriculture & Technology, 2-24-16 Naka-cho, Koganei-shi, Tokyo 184-8588, Japan.
Mol Neurodegener. 2010 May 20;5:20. doi: 10.1186/1750-1326-5-20.
Parkinson's disease (PD) involves the selective damage of dopaminergic neuron cells resulting from the accumulation and fibril formation of alpha-synuclein. Recently, it has been shown that not only full-length alpha-synuclein, but also C-terminal truncated forms exist in the normal brain, as well as Lewy bodies, which are cytoplasmic inclusions in PD. It is known that truncated alpha-synuclein has a much higher ability to aggregate and fibrillate than full-length alpha-synuclein. Since the fibrils and precursor oligomers of alpha-synuclein are cytotoxic to the neuron, inhibitors that prevent the formation of oligomers and/or fibrils might open the way to a novel therapeutic approach to PD. However, no inhibitor for truncated alpha-synuclein has been reported yet.
In this study, we first characterized the aggregation and cytotoxicity of C-truncated alpha-synuclein119 and alpha-synuclein133 which have been found in both the normal and the pathogenic brain. Alpha-synuclein119 aggregated more rapidly and enhanced significantly the fibril formation of alpha-synuclein. Although both of alpha-synuclein119 and alpha-synuclein133 showed a high cytotoxicity, alpha-synuclein133 showed a similar aggregation with full-length alpha-synuclein and no acceleration effect. We showed that PQQ dramatically inhibits the fibril formation of C-terminal truncated alpha-synuclein110119, and 133 as well as the mixtures of full-length alpha-synuclein with these truncated variants. Moreover, PQQ decreases the cytotoxicity of truncated alpha-synuclein.
Our results demonstrate that PQQ inhibits the amyloid fibril formation and cytotoxicity of the C-truncated alpha-synuclein variants. We believe that PQQ is a strong candidate for a reagent compound in the treatment of PD.
帕金森病（PD）涉及多巴胺能神经元细胞的选择性损伤，这是由于α-突触核蛋白的积累和纤维形成所致。最近，研究表明，不仅全长α-突触核蛋白，而且在正常大脑中还存在 C 端截断形式，以及 PD 中的细胞质包含物路易体。众所周知，截断的α-突触核蛋白比全长α-突触核蛋白具有更高的聚集和纤维化能力。由于α-突触核蛋白的纤维和前体寡聚物对神经元具有细胞毒性，因此防止寡聚物和/或纤维形成的抑制剂可能为 PD 的新治疗方法开辟道路。但是，尚未报道用于截断的α-突触核蛋白的抑制剂。
在这项研究中，我们首先对在正常和致病大脑中均发现的 C 截断的α-突触核蛋白 119 和α-突触核蛋白 133 的聚集和细胞毒性进行了表征。α-突触核蛋白 119 聚集得更快，并显著增强了α-突触核蛋白的纤维形成。尽管α-突触核蛋白 119 和α-突触核蛋白 133 均显示出高细胞毒性，但α-突触核蛋白 133 与全长α-突触核蛋白具有相似的聚集性，并且没有加速作用。我们表明，PQQ 可显著抑制 C 末端截断的α-突触核蛋白 110119 和 133 的纤维形成，以及全长α-突触核蛋白与这些截断变体的混合物。此外，PQQ 降低了截断的α-突触核蛋白的细胞毒性。
我们的结果表明，PQQ 可抑制 C 截断的α-突触核蛋白变体的淀粉样纤维形成和细胞毒性。我们相信 PQQ 是治疗 PD 的候选试剂化合物。
