Expanding the Guanosine-Guanfacine Synergy: A Molecular Hypothesis Involving G-Quadruplex (G4) RNA Structures and Protein Phosphatase 2A (PP2A) in Neurodegeneration

Abstract

Abstract Multitarget therapeutic strategies represent a critical shift in treating multifactorial neurodegenerative disorders like Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). This hypothesis paper expands upon the previously proposed neuroprotective synergy between the endogenous purine nucleoside Guanosine and the \(\alpha _{2A}\)-adrenergic receptor agonist Guanfacine. Here, we introduce a novel macromolecular mechanistic layer: the competitive interaction of Guanosine with toxic G-quadruplex (G4) RNA transcripts (a primary pathological hallmark in C9orf72-linked ALS and AD) and the concomitant allosteric modulation of Protein Phosphatase 2A (PP2A) via its constant subunit PPP2R1A. We hypothesize that while Guanfacine stabilizes prefrontal networks and dampens microglial neuroinflammation, Guanosine exerts a dual role by destabilizing neurotoxic G4 aggregates and preventing Tau hyperphosphorylation through PP2A rescue. This conceptual framework establishes a structural and biophysical rationale intended to guide upcoming in silico macromolecular docking and subsequent in vitro contract research validation. Keywords: Guanosine; Guanfacine; G-quadruplex (G4); Protein Phosphatase 2A (PP2A); PPP2R1A; Neurodegeneration; Multitarget Synergy.