Development of Therapeutic Agents Targeting Higher-order Structures of Nucleic Acids in Neurodegenerative Diseases

Abstract

G-quadruplex (G4) is a unique nucleic acid structure that formed when a four-stranded structure is produced within a single-stranded guanine-rich sequence. Four guanine molecules form a square planar arrangement, termed G-quartet, which are stacked on top of each other to form the G4 structure in DNA (G4DNA) and in RNA (G4RNA). Recent studies have revealed that G4DNA and G4RNA are folded in cells, which suggested their biological and pharmacological significance in DNA replication, transcription, epigenetic modification, and RNA metabolism. In this review, I will provide an overview of G4, its identification methods, and the biological functions “G4 biology” that have been reported, as well as its relevance to the neurological diseases that we have reported. 1) we found a neuropathogenic mechanism, “G4 prionoids” in a CGG triplet repeat disease, Fragile X-associated tremor/ataxia syndrome (FXTAS). 2) G4 is a target of cognitive function therapy for ATR-X intellectual disability syndrome, in which mutations are found in a G4 binding protein ATRX. 3) 5-aminolevulinic acid is a potential candidate drug for treating some neurological diseases through the G4 binding ability.