Lysosomal stress triggers exosome release and transfer of proteins

 描述（由申请人提供）：自噬-溶酶体应激促进蛋白质的外泌体释放和转移自噬-溶酶体功能障碍与神经退行性疾病如帕金森病和阿尔茨海默病有关，有强有力的证据表明，在衰老和疾病中，这种主要的蛋白质/脂质质量控制途径是无效的。与可能导致溶酶体应激的基因突变（包括帕金森氏症和相关疾病中葡萄糖脑苷脂酶（GC）功能降低）的相关性日益增加。净效应是溶酶体活性降低，这可能有助于多余蛋白质的积累和功能失调的细胞器。 虽然大多数蛋白质被保留在内部并作为聚集体隔离，但最近的研究表明，像α-突触核蛋白和tau蛋白这样的蛋白质可以从一个细胞传播到另一个细胞，或者从一个区域传播到另一个区域。病理的传递可能是神经元增强自我保护机制的机会，将潜在的毒性蛋白质挤出到细胞外环境中。我们有证据表明，化学诱导的溶酶体应激可以增加外泌体形式的细胞外释放，并可能含有蛋白毒性元素。外泌体是从大多数细胞释放的细胞内囊泡，其容易被吸收到受体细胞中，并且可以代表蛋白质的病理转移的介质。此外，当存在溶酶体应激时，外泌体释放可能相对于游离蛋白质释放显著增加。在这个项目中，我们研究了溶酶体应激在外泌体产生和货物转移到附近细胞中的作用，作为连接神经变性和病理学传播中看到的溶酶体功能障碍的模型。我们采用互补的细胞，动物和人类基板，以表征这种生物和puerperous神经病理学事件。

 DESCRIPTION (provided by applicant): Autophagic-Lysosomal Stress Promotes Exosomal Release and Transfer of Proteins Autophagic-lysosomal dysfunction has been linked to neurodegenerative diseases like Parkinson's and Alzheimer's disease with strong evidence indicating that in aging and disease, this major protein/lipid quality control pathway is inefficiet. There is increasing association with genetic mutations that may contribute to lysosomal stress, including reduction in glucocerebrosidase (GC) function in Parkinson's and related disorders. The net effect is reduced lysosomal activity that may contribute to the accumulation of redundant proteins and dysfunctional organelles. While most proteins are retained internally and sequestered as aggregates, recent work has shown that proteins like a-synuclein and tau can spread from one cell to another, or from one region to another. The transmission of pathology may be an opportunity for neurons to enhance self- preservation mechanisms extruding potentially toxic proteins into the extracellular milieu. We have evidence that chemically-induced lysosomal stress can increase the extracellular release in the form of exosomes and may contain proteotoxic elements. Exosomes are intracellular vesicles released from most cells that are readily taken into recipient cells and may represent a medium for pathological transfer of proteins. Further, it is likely that exosomal release is significantly increased versus free protein release when there is lysosomal stress. In this project we examine the role of lysosomal stress in exosomal production and transfer of cargo to nearby cells as a model linking lysosomal dysfunction seen in neurodegeneration and the transmission of pathology. We employ complimentary cell, animal and human substrates to characterize this biological and putatively neuropathological event.