RNA G-quadruplex-protein interactions: from nuclear RNA processing to cytoplasmic stress response and neurodegeneration

RNA G-quadruplexes (rG4s) are stable secondary structures formed by non-canonical Hoogsteen base-pairing of guanine-rich sequences in precursor and mature messenger and non-coding RNAs. We review evidence that rG4s exist in two functionally distinct worlds. In the nucleus, rG4s fold co-transcriptionally to regulate gene expression and RNA processing and organizing membraneless organelles through liquid-liquid phase separation. Splicing regulation by rG4s is restricted to vertebrates and co-evolved with transcriptome complexity. In the cytoplasm, rG4s are actively maintained in an unfolded state by dedicated helicases and RNA-binding proteins, but fold upon stress to nucleate stress granules, that sequester mRNAs and sustain cell survival. When compartmentalization of rG4-protein interactions fails, cells lose both nuclear RNA processing control and cytoplasmic translational regulation and proper stress response. The same biophysical properties that make rG4s effective scaffolds for reversible phase separation in RNA processing, proteostasis, and acute stress become liabilities under chronic conditions: in ageing neurons, failure of rG4-protein homoeostasis transforms protective condensates into irreversible aggregates associated with α-synuclein, tau, TDP-43, and FUS pathology. We discuss the implications of a dynamic equilibrium of folded and unfolded rG4s in health and disease, with particular focus on their emerging roles in neurodegeneration.