Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine,ACS Chemical Biology

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Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-06-28 00:00:00 , DOI: 10.1021/acschembio.8b00466
Michele Perni _{1,

2} , Patrick Flagmeier _{1,

2} , Ryan Limbocker _{1,

2} , Roberta Cascella ₃ , Francesco A. Aprile _{1,

2} , Céline Galvagnion _{1,

4} , Gabriella T. Heller _{1,

2} , Georg Meisl _{1,

2} , Serene W. Chen _{1,

2} , Janet R. Kumita _{1,

2} , Pavan K. Challa _{1,

2} , Julius B. Kirkegaard ₅ , Samuel I. A. Cohen _{1,

2} , Benedetta Mannini _{1,

2} , Denise Barbut ₆ , Ellen A. A. Nollen ₇ , Cristina Cecchi ₃ , Nunilo Cremades ₈ , Tuomas P. J. Knowles _{1,

2,

9} , Fabrizio Chiti ₃ , Michael Zasloff _{6,

10} , Michele Vendruscolo _{1,

2} , Christopher M. Dobson _{1,

2}

Affiliation

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
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy
German Centre for Neurodegenerative Diseases, DZNE, Sigmund-Freud-Strasse. 27, 53127, Bonn, Germany
Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, United Kingdom
Enterin Inc., 3624 Market Street, Philadelphia, Pennsylvania 19104, United States
University Medical Centre Groningen, European Research Institute for the Biology of Aging, University of Groningen, Groningen 9713 AV, The Netherlands
Institute for Biocomputation and Physics of Complex Systems (BIFI)-Joint Unit BIFI-IQFR (CSIC), University of Zaragoza, 50018 Zaragoza, Spain
Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, United Kingdom
MedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, DC 20010, United States

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.

中文翻译：

α突触核蛋白聚集和毒性的多步抑制在体外和体内由Trodusquemine

α-突触核蛋白（一种在神经元中高度丰富的内在失调的蛋白质）的聚集与帕金森氏病的发作和发展密切相关。先前我们已经证明氨基固醇角鲨胺可以抑制脂质诱导的α-突触核蛋白聚集过程，并且我们在这里报道了相关化合物trodusquemine不仅可以抑制该过程，而且还可以抑制原纤维依赖的次级途径。聚集反应。我们进一步证明，trodusquemine可以有效抑制神经元细胞中α-突触核蛋白寡聚体的毒性，即使在最初的生长期之后，曲妥斯克明的给药也会导致秀丽隐杆线虫中α-突触核蛋白包涵体的数量急剧减少。帕金森氏病模型，消除了相关的肌肉麻痹，并延长了寿命。基于这些发现，我们表明，曲妥司明能够抑制α-突触核蛋白的聚集过程中的多个事件，因此能够提供有关此类事件与神经退行性变之间的联系的重要信息，因为它的发生和发展都非常重要。特别是鉴于先前报道的曲妥斯明能穿越血脑屏障并促进组织再生的能力，本发明结果表明该化合物具有成为帕金森氏病和相关疾病的重要治疗候选物的潜力。

更新日期：2018-06-28

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