Höllerhage Matthias, Goebel Joachim N, de Andrade Anderson, Hildebrandt Tobias, Dolga Amalia, Culmsee Carsten, Oertel Wolfgang H, Hengerer Bastian, Höglinger Günter U
German Center for Neurodegenerative Diseases (DZNE), Department of Translational Neurodegeneration, Munich, Germany; Department of Neurology, Technical University of Munich, Munich, Germany; Experimental Neurology, University of Marburg, Marburg, Germany.
Experimental Neurology, University of Marburg, Marburg, Germany.
Neurobiol Aging. 2014 Jul;35(7):1700-11. doi: 10.1016/j.neurobiolaging.2014.01.027. Epub 2014 Jan 28.
Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Presently, there is no causal therapy available to slow down or halt disease progression. The presynaptic protein alpha-synuclein aggregates to form intraneuronal Lewy bodies in PD. It is generally believed that intermediates on the way from monomers to the large aggregates would mediate neurotoxicity, but the precise species and mechanism responsible for neuronal death are controversially debated. To study alpha-synuclein-mediated toxicity, we developed a new model in which moderate overexpression of wild-type alpha-synuclein led to gradual death of human postmitotic dopaminergic neurons. In accordance with findings in postmortem PD brains, small oligomeric species occurred and the autophagic flux was impaired in our model. The phenothiazine neuroleptic trifluoperazine, an activator of macroautophagy, selectively reduced one particular alpha-synuclein species and rescued cells. Inversely, blocking of autophagy led to an accumulation of this oligomeric species and increased cell death. These data show that activation of autophagy is a promising approach to protect against alpha-synuclein pathology and likely acts by targeting one specific alpha-synuclein species.
帕金森病（PD）是最常见的神经退行性运动障碍。目前，尚无能够减缓或阻止疾病进展的病因疗法。在帕金森病中，突触前蛋白α-突触核蛋白聚集形成神经元内路易小体。人们普遍认为，从单体到大型聚集体过程中的中间体介导神经毒性，但导致神经元死亡的确切物质和机制仍存在争议。为了研究α-突触核蛋白介导的毒性，我们开发了一种新模型，其中野生型α-突触核蛋白的适度过表达导致人有丝分裂后多巴胺能神经元逐渐死亡。与帕金森病死后大脑的研究结果一致，我们的模型中出现了小的寡聚体物质，并且自噬通量受损。吩噻嗪类抗精神病药物三氟拉嗪是一种巨自噬激活剂，它选择性地减少了一种特定的α-突触核蛋白物质并拯救了细胞。相反，阻断自噬会导致这种寡聚体物质的积累并增加细胞死亡。这些数据表明，激活自噬是预防α-突触核蛋白病理的一种有前景的方法，并且可能通过靶向一种特定的α-突触核蛋白物质起作用。
