RNA derived from cancer cells as a scaffold for amyloid-β25-35 aggregation: the effect of RNA methylation and rRNA status.

Besides a well-established protein aggregation-mediated pathologies in neurodegenerative diseases, protein misfolding and subsequent accumulation of non-functional aggregates may also have a role during cancer progression promoting cancer cell survival and affecting drug responses. A number of factors may modulate the process of protein aggregation. However, the role of RNA as a scaffold and its methylation status were not elucidated yet. In the present study, we have used a cellular model of cancer, namely osteosarcoma (OS) cells to investigate RNA-mediated amyloid-β (Aβ) aggregation in the biological system not related to Aβ-mediated pathology. In the presence of Aβ25-35, RNA isolated from OS cells promoted the formation of protein aggregates in a concentration-dependent manner in vitro. Drug-induced senescent OS cells devoid of two m5C RNA methyltransferases TRDMT1 and NSUN2 had limited ability to form protein aggregates. Nevertheless, this observation was associated with rRNA status and the expression of rRNA-related genes rather than RNA methylation. In contrast, RNA secreted by senescent wild type (WT) OS cells was characterized by increased m5C levels compared to RNA intracellular pools that was accompanied by its ability to stimulate the formation of Aβ25-35 aggregates. In conclusion, we show for the first time that RNA derived from cancer cells may be a scaffold promoting the formation of Aβ25-35 aggregates. More studies are needed to validate the RNA-mediated protein aggregation in cellular systems and its modulation by RNA methylation and rRNA status. RNA amyloidogenic activity should also be assessed in the presence of full-length Aβ.