Dementia, one of the leading causes of death worldwide, encompasses a variety of neurodegenerative diseases, with Alzheimer’s disease (AD) accounting for an estimated 60-80% of all cases1. One of the neuropathological features of AD is the glial response with emphasis on astrocyte reactivity. Major players in neuronal homeostasis, astrocytes are known to be involved in amyloid-β pathways and the inflammatory response in AD2.
The DNA/RNA binding protein FUS (Fused in Sarcoma) is highly associated with neurodegenerative diseases such as ALS and FTLD but has not been investigated to the same degree in AD 3. FUS has been shown to interact with RNA G-quadruplexes (G4s)4. These non-canonical secondary structures that form in certain G-rich regions of nucleic acids are involved in regulation of gene expression and are consequently implicated in disease development and/or progression5.
This study investigates the interactions between RNA G4s and FUS in cell models of AD, focusing on astrocyte glial cells. Astrocyte stimulation was assessed using cell viability assays and immunofluorescent detection of activation markers GFAP and CSPG. The effects of stimulation on AD-related genes APP, MAPT, and FUS, and RNA G4 formation were examined through qPCR and immunofluorescence, respectively. Furthermore, G4-stabilising ligands were used to investigate whether G4s lead to alterations in levels of APP, MAPT, and FUS, suggesting involvement in AD-related gene expression. FUS knock-down using siRNA was used to examine the resulting effects on RNA G4 formation, and APP, and MAPT.