Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form
Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form
复制标题
DOI：
10.1016/j.nbd.2017.07.007
复制
发表时间：
2017-10-01
影响因子：
6.1
通讯作者：
Paumier, Katrina L.
中科院分区：
文献类型：
--
作者：
Collier, Timothy J.;Srivastava, Kinshuk R.;Paumier, Katrina L.
帕金森病和其他突触核蛋白病的病理学特征在于主要由错误折叠的纤维状α-突触核蛋白（α-syn）组成的细胞内内含物的形成。减缓疾病进展的一种策略是防止其天然单体形式的错误折叠和聚集。在这里，我们提出的研究结果，支持的论点，三环类抗抑郁药化合物去甲替林（NOR）的突触核蛋白病的疾病修饰潜力。来自体外聚集和动力学测定的发现支持以下观点：NOR通过直接结合至可溶性单体形式来抑制α-syn的聚集，并且通过增强单体的重构来抑制蛋白质的毒性构象的形成。我们继续证明NOR在多细胞和动物模型中抑制α-syn的积累、聚集和神经毒性。这些发现表明，NOR，一种具有治疗抑郁症的安全性和有效性的化合物，可以通过直接结合可溶性天然α-syn来减缓α-syn病理学的进展，从而抑制病理性聚集并保持其正常功能。(C)2017爱思唯尔公司All rights reserved.
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar alpha-synuclein (alpha-syn). One strategy to slow disease progression is to prevent the misfolding and aggregation of its native monomeric form. Here we present findings that support the contention that the tricyclic antidepressant compound nortriptyline (NOR) has disease-modifying potential for synucleinopathies. Findings from in vitro aggregation and kinetics assays support the view that NOR inhibits aggregation of alpha-syn by directly binding to the soluble, monomeric form, and by enhancing reconfiguration of the monomer, inhibits formation of toxic conformations of the protein. We go on to demonstrate that NOR inhibits the accumulation, aggregation and neurotoxicity of alpha-syn in multiple cell and animal models. These findings suggest that NOR, a compound with established safety and efficacy for treatment of depression, may slow progression of alpha-syn pathology by directly binding to soluble, native, alpha-syn, thereby inhibiting pathological aggregation and preserving its normal functions. (C) 2017 Elsevier Inc. All rights reserved.