The role of human endogenous retroviral RNA as an activator of Toll-like receptors in neurodegeneration

中枢神经系统（CNS）损伤可通过内源性因子激活先天免疫受体而加重。然而，这些因子的身份，所涉及的信号通路，以及所涉及的细胞生物学机制仍然是难以捉摸的。脊椎动物的基因组含有内源性逆转录病毒，这些病毒主要是外源性逆转录病毒感染祖先种系的无功能残留物。尽管人类内源性逆转录病毒因子（HERV）在人类基因组中占相当大的比例，但人们对其生物学功能知之甚少。HERV-K是最近进入人类基因组的病毒，其亚群HERV-K（HML-2）包含许多人类特异性前病毒，其中一些在大脑中具有转录活性。基于我们之前的发现，我们假设HERV-K（HML-2）衍生的RNA激活免疫细胞中表达的toll样受体（TLRs），但也在中枢神经系统的神经元中表达。HERV-K（HML-2）衍生的RNA可能作为tlr的损伤相关信号分子，因此可能有助于中枢神经系统损伤的扩散，而与各自疾病的初始原因无关。详细地说，我们将首先更精确地表征HERV-K(HML-2) RNA作为tlr的潜在内源性配体。这些实验将为研究HERV-K（HML-2）激活TLR在阿尔茨海默病等神经炎症和神经退行性疾病中的作用提供基础。该项目的目的是确定HERV-K（HML-2）衍生的RNA作为内源性TLRs激活剂在神经退行性过程中的作用。确定潜在的分子机制可能为开发新的治疗策略开辟道路。

Central nervous system (CNS) injury can be exacerbated through activation of innate immune receptors by endogenous factors. However, the identity of such factors, the involved signaling pathways, and the cell biological mechanisms involved remain elusive. The genomes of vertebrates contain endogenous retroviruses, which are largely nonfunctional relicts of ancestral germline infection by exogenous retroviruses. Although human endogenous retroviral elements (HERV) represent a substantial proportion of the human genome, little is known about their biological function. HERV-K represents the most recent entry into the human genome, and its subgroup HERV-K(HML-2) comprises numerous human-specific proviruses of which several can be transcriptionally active in the brain. Based on our previous findings, we hypothesize that HERV-K(HML-2)-derived RNA activates Toll-like receptors (TLRs) expressed in immune cells but also in neurons of the CNS. HERV-K(HML-2)-derived RNA may serve as an injury-related signaling molecule for TLRs and may thereby contribute to the spread of CNS damage, independently of the initial cause of the respective disease. In detail, we will first characterize HERV-K(HML-2) RNA as a potential endogenous ligand of TLRs more precisely. These experiments will provide a basis for the investigation of the role of TLR activation by HERV-K(HML-2) in the context of neuroinflammation and neurodegeneration, such as Alzheimers disease. The aim of the project is to determine the role of HERV-K(HML-2)-derived RNA as an endogenous activator of TLRs in neurodegenerative processes. Identification of the underlying molecular mechanisms may open the way to the development of new therapeutic strategies.