Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , United Kingdom.
Centre for Misfolding Diseases, Department of Chemistry , University of Cambridge , Cambridge CB2 1EW , United Kingdom.
ACS Chem Biol. 2018 Aug 17;13(8):2308-2319. doi: 10.1021/acschembio.8b00466. Epub 2018 Jun 28.
The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely associated with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compound trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic reduction in the number of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of α-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compound has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.
α-突触核蛋白的聚集与帕金森病的发病和进展密切相关，α-突触核蛋白是一种在神经元中高度丰富的固有无序蛋白。我们之前已经表明，氨基甾醇鲨烯胺可以抑制α-突触核蛋白聚集过程中脂质诱导的起始过程，我们在这里报告说，相关化合物曲多沙胺不仅能够抑制这个过程，还能够抑制聚集反应中纤维依赖性的次级途径。我们进一步证明，曲多沙胺可以有效地抑制神经元细胞中α-突触核蛋白寡聚物的毒性，并且即使在初始生长阶段后进行给药，也会导致秀丽隐杆线虫帕金森病模型中α-突触核蛋白包涵体的数量显著减少，消除相关的肌肉麻痹，并延长寿命。基于这些发现，我们表明曲多沙胺能够抑制α-突触核蛋白聚集过程中的多个事件，从而为这些事件与神经退行性变之间的联系提供了重要信息，因为它是由起始和进展引起的。特别是考虑到曲多沙胺以前被报道能够穿过血脑屏障并促进组织再生，目前的结果表明，该化合物有可能成为帕金森病和相关疾病的重要治疗候选药物。
