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

• Applicant: Professorin Dr. Seija Lehnardt
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 356501535

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.

• DFG Programme: Research Grants