Selective aptamer probe for detecting and targeting multimolecular G-quadriplexes aggregates in amyotrophic lateral sclerosis (ALS) disease

G-quadruplex structures (G4s) are gaining attention due to their widespread presence in the human genome, featuring over 700,000 identified sequences. These stable G4s are often found in critical areas of our DNA, such as telomeres, gene promoters, and regions linked to repeat expansions in diseases.However, when investigating their biological function, multimolecular G-quadruplexes (mG4s) have been often overlooked and deemed unlikely to be physiologically relevant, with the bulk of recent advances on G4-biology almost exclusively focused on unimolecular G-quadriplexes (uG4s).SPOTTER aims to fill this critical gap in the biology of mG4, by generating a selective probe that is currently missing to study these structures. Specifically, in this proposal, an aptamer-based probe that can be tuned to interact exclusively with mG4s will be developed.This tool will facilitate live-cell imaging and genome-wide mapping of mG4s for the very first time. This will further allow me to explore the role of mG4 formed in guanine-rich RNA repeat expansions, which could trigger formation of insoluble aggregates that are relevant to neurodegenerative diseases, such as in amyotrophic lateral sclerosis (ALS).