Initiation and propagation of alpha synuclein oligomers--Relevance for Parkinson s disease

α突触核蛋白寡聚体的起始和增殖——与帕金森病的相关性

• 批准号: 282604822
• 负责人: Professorin Dr. Karin Danzer
• 金额: --
• 依托单位: Standort Ulm
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282604822?language=en
• 关键词: Initiation; propagation; alpha; synuclein; oligomers

Parkinsons disease (PD) pathogenesis is characterized by initiation and propagation of alpha synuclein (asyn) pathology. Recent evidence suggests that some forms of asyn are secreted from neurons and taken up by neighboring neurons, thereby suggesting that extracellular asyn species might be toxic in PD. The overall goal of this proposal is to study the underlying mechanism of initiation and propagation of PD pathology based on three lines of investigation. The first approach will study initiation and propagation processes of asyn pathology on the protein level. Here we will investigate cell-to-cell- transmission of asyn oligomers in vitro and in vivo. For this purpose we have generated an innovative animal model based on a split protein complementation assay that allows measurement of asyn oligomers in a highly sensitive way in vivo. In our initial experiments, we found in cell culture that asyn species can form toxic oligomeric species in the extracellular space which are released in association with exosomes or free. We also found that these oligomeric species can be taken up by neurons and act as a nidus for additional oligomer formation. We will now identify the pathologically relevant asyn species responsible for propagation in vitro and in vivo. We will investigate the prion-like transmission of asyn oligomers from neuron to neuron via exosomes and free asyn in vivo. In the second line of investigation we will explore the transmission of asyn oligomers to non-neuronal cells more precisely immune cells. We previously found hyperactive monocytes in the peripheral blood of PD patients but the role of asyn in monocytes activation is not clear yet. We therefore propose to investigate the role of different asyn forms in monocyte activation. We speculate that different extracellular asyn species in free form or associated with exosomes might be an effective trigger for stimulation and/or pre-conditioning of monocytes in the blood of PD patients. As asyn may not be the only transmitting molecular substrate responsible for spreading of disease pathology, we will test in the third line of investigation the hypothesis that transmission of pathology also partially consist of a non-proteinaccious species, e.g. coding or non-coding RNA molecules. We will therefore explore whether coding or non-coding RNA molecules associated to exosomes or free contribute to reprogramming of neighboring cells. Together, in this project we will implement complementary approaches to elucidate the fundamental mechanisms of initiation and propagation of asyn pathology. If this research program will be successful it will directly impact clinical diagnostics in PD and will open new avenues for unique therapeutic interventions for PD and other neurodegenerative diseases.

帕金森病（PD）的发病机制的特点是启动和传播的α突触核蛋白（asyn）的病理。最近的证据表明，某些形式的asyn从神经元分泌并被邻近的神经元吸收，从而表明细胞外asyn种类可能在PD中是有毒的。本提案的总体目标是基于三条调查线研究PD病理的启动和传播的潜在机制。第一种方法将在蛋白质水平上研究asyn病理的起始和传播过程。在这里，我们将研究细胞间的传递asyn寡聚体在体外和体内。为此，我们已经产生了一个创新的动物模型的基础上分裂蛋白互补测定，允许测量asyn寡聚体在体内以高度灵敏的方式。在我们最初的实验中，我们在细胞培养中发现asyn种类可以在细胞外空间中形成有毒的寡聚物种类，其与外泌体结合或游离释放。我们还发现，这些寡聚物物种可以采取的神经元和作为一个巢额外的寡聚物形成。我们现在将确定负责体外和体内繁殖的病理相关的asyn物种。我们将在体内研究asyn寡聚体通过外泌体和游离asyn从神经元到神经元的朊病毒样传递。在研究的第二条线中，我们将探索asyn寡聚体向非神经元细胞更准确地说是免疫细胞的传递。我们以前在PD患者外周血中发现了过度活跃的单核细胞，但asyn在单核细胞活化中的作用尚不清楚。因此，我们建议研究不同的asyn形式在单核细胞活化中的作用。我们推测游离形式或与外泌体相关的不同细胞外asyn种类可能是PD患者血液中单核细胞刺激和/或预处理的有效触发因素。由于asyn可能不是负责疾病病理传播的唯一传递分子底物，因此我们将在第三条研究路线中检验病理传播也部分由非蛋白质类物质（例如编码或非编码RNA分子）组成的假设。因此，我们将探索与外泌体相关的编码或非编码RNA分子是否有助于邻近细胞的重编程。在这个项目中，我们将共同实施互补的方法来阐明asyn病理学的启动和传播的基本机制。如果这项研究计划取得成功，它将直接影响PD的临床诊断，并将为PD和其他神经退行性疾病的独特治疗干预开辟新的途径。