Lysosomal stress triggers exosome release and transfer of proteins

溶酶体应激触发外泌体释放和蛋白质转移

• 批准号: 9112121
• 负责人: Ho WH Yu
• 金额: $ 23.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112121
• 关键词: ATP phosphohydrolase; Address; Aging; Alzheimer' s Disease; Animals; Area; Biological; Biological Markers; Biological Preservation; Catabolism; Cell Death; Cell Survival; Cells; Complex; DNA Sequence Alteration; Defense Mechanisms; Disease; Disease Progression; Elements; Engineering; Event; Exocytosis; Extracellular Protein; Functional disorder; Garbage; Gaucher Disease; Heterozygote; Hippocampus (Brain); Homozygote; Human; Individual; Knock-out; Lead; Link; Lipids; Lysosomes; Measurement; Messenger RNA; Modeling; Movement; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organelles; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phase; Poison; Population; Prions; Production; Protease Inhibitor; Proteins; Quality Control; RNA; Role; Route; Sphingomyelinase; Stress; Susceptibility Gene; Testing; Therapeutic; Thinking; Toxic effect; Transgenic Organisms; Triage; Vesicle; Vulnerable Populations; Work; alpha synuclein; base; brain cell; dopaminergic neuron; exosome; extracellular; genetic linkage; glucosylceramidase; human tissue; induced pluripotent stem cell; knock-down; mind control; mutant; neuronal survival; presenilin; protein aggregate; public health relevance; response; synuclein; tau Proteins; transmission process; vesicular release

 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.

 描述(由申请人提供)：自噬-溶酶体应激促进蛋白质的胞外释放和转移自噬-溶酶体功能障碍与帕金森氏症和阿尔茨海默病等神经退行性疾病有关，有强有力的证据表明，在衰老和疾病中，这一主要的蛋白质/脂肪质量控制途径效率低下。有越来越多的基因突变可能导致溶酶体应激，包括帕金森病和相关疾病中葡萄糖脑苷酶(GC)功能的降低。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以聚集体的形式隔离，但最近的研究表明，像α-突触核蛋白和tau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，将潜在的有毒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能以外切体的形式增加细胞外释放，并可能含有蛋白毒性成分。胞外体是从大多数细胞释放的胞内小泡，很容易被带进受体细胞，可能是蛋白质病理性转移的媒介。此外，当存在溶酶体应激时，胞外体的释放与游离蛋白的释放相比可能显著增加。在这个项目中，我们研究了溶酶体应激在胞外体产生和将货物转移到附近细胞中的作用，作为一个将神经变性中的溶酶体功能障碍与病理传递联系起来的模型。我们使用互补的细胞、动物和人类底物来描述这一生物学和可能的神经病理事件。