Autophagy modulates alpha-Synuclein cellular pathology and exosome associated release

自噬调节 α-突触核蛋白细胞病理学和外泌体相关释放

• 批准号: 317761452
• 负责人: Professor Dr. Jochen Klucken
• 金额: --
• 依托单位: Research Group Digital Medicine
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/317761452?language=en
• 关键词: Autophagy; modulates; alpha; Synuclein; cellular

Synucleinopathies including Parkinson disease (PD) and Dementia with Lewy bodies (DLB) are characterized by cytoplasmic and neuritic inclusions (Lewy bodies, LBs, and Lewy neurites, LNs) composed of misfolded and aggregated forms of alpha-synuclein aSyn. Complementary to the ubiquitin-proteasome degradation system (UPS) aSyn is degraded by the autophagy-lysosomal pathway (ALP). Recently, we analyzed the role of the ALP on aggregated forms of aSyn in vitro and in vivo models of aSyn aggregation where we identified a direct role of ALP not only on aSyn aggregation and toxicity, but surprisingly also to extracellular release of aSyn (Autophagy 2012, 2014). The multivesicular body compartment (MVB) might be the interconnecting cellular mechanism that links intracellular degradation to extracellular release and pathology. Since exosomes derive form MVB and have recently associated with aSyn release mechanisms, the present grant aims to understand if 1) ALP modulation affects intracellular aSyn pathology and induces exosome-dependent aSyn release mechanisms, 2) toxic aSyn species released by the exosome secretion pathway (ESP) derived from the MVB intersect with the autophagy modulated degradation pathways (ALP), and 3) if ALP and ESP modulation affects the extracellular response of neuronal (propagation) and glial cells (proinflammation) to released aSyn and thereby contributes to its pathomechanism. Intracellular pathology, extracellular release and response to neural cells will be studied in human aSyn cell culture models. In parallel, a second set of experiments will test these effects in primary neuronal cultures from human aSyn promoter driven aSyn transgenic mice (on aSyn k.o. background), and in neural cocultures. In summary, the proposed project will integrate the important role of ALP on intracellular aSyn with the recently identified role of extracellular aSyn in neuronal-glial communication, transfer, toxicity, and disease progression.

突触核蛋白病包括帕金森病（PD）和路易小体痴呆（DLB），其特征是细胞质和神经鞘包涵体（路易小体，LBs和路易神经突，LNs）由错误折叠和聚集形式的α -突触核蛋白aSyn组成。作为泛素-蛋白酶体降解系统（UPS）的补充，aSyn通过自噬-溶酶体途径（ALP）降解。最近，我们在体外和体内的aSyn聚集模型中分析了ALP对aSyn聚集形式的作用，我们发现ALP不仅对aSyn聚集和毒性有直接作用，而且令人惊讶的是，它还对aSyn的细胞外释放有直接作用（Autophagy 2012, 2014）。多泡体隔室（MVB）可能是连接细胞内降解与细胞外释放和病理的相互联系的细胞机制。由于外泌体来源于MVB，并且最近与aSyn释放机制相关，本项目旨在了解是否1)ALP调节影响细胞内aSyn病理并诱导外泌体依赖的aSyn释放机制，2)由MVB衍生的外泌体分泌途径（ESP）释放的有毒aSyn物种与自噬调节降解途径（ALP）相交，3) ALP和ESP的调节是否影响神经元（繁殖）和胶质细胞（促炎）对释放的aSyn的细胞外反应，从而参与其病理机制。细胞内病理，细胞外释放和对神经细胞的反应将在人类aSyn细胞培养模型中进行研究。与此同时，第二组实验将在人类aSyn启动子驱动的aSyn转基因小鼠的原代神经元培养物（在aSyn k.o.背景下）和神经共培养物中测试这些效果。总之，拟议的项目将整合ALP在细胞内aSyn中的重要作用，以及最近发现的细胞外aSyn在神经元-胶质通讯、转移、毒性和疾病进展中的作用。