Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Mercy Health Hauenstein Neuroscience Center, Grand Rapids, MI, USA.
Department of Physics and Astronomy, Michigan State University, East Lansing, MI, USA.
Neurobiol Dis. 2017 Oct;106:191-204. doi: 10.1016/j.nbd.2017.07.007. Epub 2017 Jul 12.
The pathology of Parkinson's disease and other synucleinopathies is characterized by the formation of intracellular inclusions comprised primarily of misfolded, fibrillar α-synuclein (α-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 α-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 α-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 α-syn pathology by directly binding to soluble, native, α-syn, thereby inhibiting pathological aggregation and preserving its normal functions.
帕金森病和其他突触核蛋白病的病理学特征是形成主要由错误折叠、纤维状α-突触核蛋白（α-syn）组成的细胞内包涵体。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三环类抗抑郁药化合物去甲替林（NOR）具有突触核蛋白病的疾病修饰潜力的观点。体外聚集和动力学测定的结果支持 NOR 通过直接结合可溶性单体形式来抑制α-syn 聚集的观点，并通过增强单体的重排，抑制蛋白的毒性构象形成。我们接着证明 NOR 抑制多种细胞和动物模型中α-syn 的积累、聚集和神经毒性。这些发现表明，NOR 是一种已被证明对抑郁症治疗安全有效的化合物，它可能通过直接结合可溶性、天然的α-syn 来减缓α-syn 病理学的进展，从而抑制病理性聚集并保留其正常功能。
