Function of exosomes in neurodegenerative diseases

外泌体在神经退行性疾病中的功能

• 批准号: 200983110
• 负责人: Professorin Dr. Anja Schneider
• 金额: --
• 依托单位: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200983110?language=en
• 关键词: Function; exosomes; neurodegenerative; diseases

Exosomes are 50-100 nm small vesicles which are secreted by a variety of cells. They can transfer genetic information, signalling proteins and pathogens such as HIV or prions between cells. Intercellular transmission of disease pathology has also been discussed in the context of neurodegenerative disorders. This was prompted by the finding that transplanted fetal neurons in Parkinson’s disease patients began to accumulate the intraneuronal alpha-synuclein aggregates that define the disease, indicating propagation of pathology from host to graft neurons. It is well established that aggregates of alpha-synuclein can act as seeds to trigger the aggregation of monomeric alpha-synuclein. Interneuronal transfer of alpha-synuclein oligomers could therefore induce aggregation in the host neuron and contribute to the dissemination of aggregates throughout the brain. We have shown that exosomes from neuronal cultures are enriched in oligomeric alphasynuclein. Therefore we propose that exosomes can act as “Trojan horses” in the transneuronal propagation of aggregates in neurodegenerative diseases. We will study the cellular machinery involved in targeting of aggregated proteins into exosomes, their release and internalisation by host neurons as well as exosome-mediated toxicity in host neurons. The in vivo relevance of exosomal disease propagation will be assessed by microinjection of synuclein containing exosomes derived from tissue culture, primary fibroblasts and cerebrospinal fluid of Parkinson’s disease patients into the brains of alpha-synuclein transgenic mouse models. We will monitor whether exosome injection can transmit the disease in mice and study the routes of interneuronal exosome spreading in transgenic mouse models.

外泌体是由多种细胞分泌的50-100 nm的小泡。它们可以传递遗传信息，在细胞之间传递蛋白质和HIV或朊病毒等病原体的信号。在神经退行性疾病的背景下也讨论了疾病病理的细胞间传递。这是由于发现帕金森病患者的移植胎儿神经元开始在神经元内积聚α -突触核蛋白聚集体，这表明病理从宿主向移植神经元的传播。α -突触核蛋白的聚集可以作为触发单体α -突触核蛋白聚集的种子。因此，α -突触核蛋白寡聚物的神经元间转移可以诱导宿主神经元的聚集，并促进聚集物在整个大脑的传播。我们已经证明，来自神经元培养的外泌体富含寡聚的α核蛋白。因此，我们提出外泌体可以作为“特洛伊木马”在神经退行性疾病中聚集物的跨神经元传播。我们将研究聚集蛋白靶向外泌体的细胞机制，它们在宿主神经元中的释放和内化，以及外泌体介导的宿主神经元毒性。外泌体疾病传播的体内相关性将通过将来自组织培养、原代成纤维细胞和帕金森病患者脑脊液的含有突触核蛋白的外泌体微量注射到α -突触核蛋白转基因小鼠模型的大脑中来评估。我们将监测注射外泌体是否能在小鼠中传播疾病，并研究转基因小鼠模型中神经元间外泌体的传播途径。