Exosome-mediated propagation of disease linked poly-dipeptides in C9orf72-FTD/ALS

越来越多的证据揭示了额颞部痴呆(FTD)和 肌萎缩侧索硬化症(ALS)致病蛋白在细胞间传播。尽管很少有其他人 机制已经提出，据报道外体的分泌发生在不同的神经上。 细胞类型，包括神经元，并有可能作为一种新的细胞间通讯途径 中枢神经系统。有趣的是，基于临床的病灶和神经解剖学传播的证据 症状，还假设脑脊液(CSF)可以作为载体 致病蛋白至少在肌萎缩侧索硬化症中传播。 利用不同的体外细胞培养平台，包括来自IPSCs的脊髓运动神经元 在C9orf72患者中，我们最近了解到C9orf72连接的二肽蛋白(Dprs)分布在 神经细胞通过外切体依赖的途径。通过分析一个新产生的外显体报告 在转基因小鼠中，我们还发现外切体能够在体内进行远距离迁移。 这些观察结果使我们假设，外切体介导的dprs的传播可能是一种 有毒侮辱在C9orf72-FTD/ALS疾病困扰的中枢神经系统区域传播的方式。我们会的 利用体外和体内互补试验接近传播dprs的新假说 通过外体将损伤转移到相邻的两个细胞，也转移到突触回路下游的神经元。 我们建议：(1)研究外切体介导的dprs在中枢神经系统细胞中的传播机制； (2)研究dprs在体内的细胞间繁殖方式；(3)研究 Dprs的细胞转移会传播毒性。 拟议的工作有可能开辟C9orf72 FTD/ALS的一个全新领域 同时，研究也为了解大脑的基本生物过程提供了重要线索 与脑部疾病相关的细胞通讯。因此，预计结果将产生重大影响 对了解C9orf72相关的FTD/ALS发病机制和最终治疗患者的影响。

A growing body of evidence uncovered a propensity for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) pathogenic proteins to propagate from cell-to-cell. Although few other mechanisms have been proposed, secretion of exosomes has been reported to occur from different neural cell types, including neurons, and to potentially serve as a new intercellular communication route within the CNS. Interestingly, based on the evidence of focality and neuroanatomical propagation of clinical symptoms, it was also hypothesized that the cerebro-spinal fluid (CSF) could serve as vehicle for pathogenic proteins spread, at least in ALS. Utilizing different in vitro cell culture platforms, including spinal motor neurons derived from iPSCs of C9orf72 patients, we recently learnt that C9orf72-linked dipeptide proteins (DPRs) spread between neural cells via the exosome-dependent pathway. By analyzing a newly generated exosome-reporter transgenic mouse, we also found that exosomes are capable of migrating extensive distance in vivo. These observations led us to postulate that an exosome-mediated propagation of DPRs could be a modality by which toxic insults spread in disease-afflicted CNS areas in C9orf72-FTD/ALS. We will be testing using complementary in vitro and in vivo approaches the novel hypothesis that transmitted DPRs transfer injury via exosomes to both neighboring cells, but also to neurons downstream in synaptic circuits. We propose: (1) To investigate exosome-mediated mechanisms of DPRs transmission in CNS cells; (2) To examine the modalities of cell-to-cell propagation of DPRs in vivo; (3) To examine whether cell transfer of DPRs propagates toxicity. The proposed work has the potential to open up an entirely new field of C9orf72 FTD/ALS research, at the same time, providing important clues to the fundamental biological processes in brain cellular communications relevant to brain diseases. Thus, the results are expected to have a significant impact for understanding C9orf72-linked FTD/ALS pathogenesis and eventually treating patients.