Feedback amplification between Retrotransposons/endogenous retroviruses and TDP-43 in Alzheimers related dementias

项目摘要 这项提案调查了一种新的想法来解释TDP-43蛋白病理是如何 疾病开始后，在神经胶质细胞和神经元之间扩增和扩散。TDP-43 聚集病理是一组神经退行性疾病的核心特征 包括额颞叶痴呆、阿尔茨海默氏症和肌萎缩侧索硬化症。我们 提出并将检验反转录转座子和内源性逆转录病毒的假设 都是由TDP-43病理激活的，都可以是这种 病理学。我们还将测试这些移动元素有助于机制的想法 细胞间传播可能是疾病发展的基础。我们将使用这两种方法 果蝇模型和哺乳动物细胞培养的核心特征测试这一建议 模特。

PROJECT ABSTRACT This proposal investigates a novel idea to explain how TDP-43 protein pathology is amplified and spread between glia and neurons after initiation of disease. TDP-43 aggregation pathology is a core feature of a suite of neurodegenerative disorders including frontotemporal dementia, Alzheimer’s and amyotrophic lateral sclerosis. We propose and will test the hypothesis that retrotransposons and endogenous retroviruses are both activated by TDP-43 pathology and can be upstream initiators of such pathology. We also will test the idea that these mobile elements contribute a mechanism of inter-cellular spread that could underlie progression of disease. We will use both Drosophila models and mammalian cell culture to test the core features of this proposed model.