Year: 2024
Type: conference-abstract
Abstract: Background Glial activation and neuroinflammation are prominent features in Huntington’s disease (HD) pathogenesis, although their drivers and effects in HD progression remain unclear. Small RNAs (sRNAs) are early dysregulated in HD brains. Our previous data showed that sRNAs from HD patients’ brains (HD-sRNAs) cause neurotoxicity and neuroinflammation in vivo. Recent studies indicate that endogenous RNAs can trigger immune pathways through specific sensing machinery. Aims Our aim is to understand the role of RNA sensors and their downstream immune factors in HD, and determine the immunogenic properties of HD-sRNAs. Methods Expression of RNA sensors and inflammatory cytokines were measured by qPCR, and immunogenic effects of sRNAs were evaluated in activated THP1 cells using IL1-beta ELISA. Results We observed a significant induction of RNA sensors and inflammatory cytokines in animals injected with HD-sRNAs compared to CTL-sRNAs, and HD-sRNAs induced a pro-inflammatory response in THP1 cells, indicating an acute inflammatory response specific to HD. Additionally, RNA sensors were robustly induced in human HD brains, with most cytokines significantly overexpressed. This pro-inflammatory profile is effectively recapitulated in neurons derived from HD human embryonic stem cells. However, RNA sensor induction and the inflammatory environment are not observed in the R6/1 mouse model. Conclusions Overall, our results point to sRNAs as contributors to HD neuroinflammation. Understanding which cell type produces immunogenic sRNAs, the identity and/or biochemical properties of immunogenic sRNAs and whether their activity is a cell-autonomous mechanism are key questions that need to be resolved. These studies have a strong potential for novel therapeutic designs.
Institutions: Universitat de Barcelona, Biomedical Research Networking Center on Neurodegenerative Diseases, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Institut Pasteur de Montevideo, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Massachusetts Institute of Technology
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373726