Abstract
The RNA-induced silencing complex (RISC), built around the Argonaute proteins, executes microRNA-mediated gene silencing. AGO2, the only catalytically active human paralogue, stabilises mature microRNAs in neurons and controls local translation in dendrites and axons. AGO2 is now invoked across the whole span of neurological disease, from monogenic neurodevelopmental syndromes to Alzheimer’s and Parkinson’s disease, on evidence of very unequal strength. We therefore ask of each body of work two questions: what was experimentally manipulated, and what was then measured. De novo variants in AGO1 and AGO2 cause the Argonaute syndromes, where the mechanism has been traced from the kinetics of the mutant protein to knock-in mouse phenotypes and indicates delayed strand release rather than loss of function; conditional Ago2 deletion in mice is comparably direct for neurovascular development and adult neurogenesis. In neurodegenerative disease, the position differs. The DISE mechanism shows that AGO2 activity sets the threshold for amyloid-beta toxicity in cultured neurons, and one study identifies AGO2 as an endogenous brake on alpha-synuclein synthesis, but no experiment has yet tested whether altering AGO2 in vivo changes neurodegeneration, even though deleting the upstream enzyme Dicer kills dopaminergic neurons. Benchmarked against TDP-43-dependent mis-splicing, where causality in amyotrophic lateral sclerosis is established, AGO2 remains a convergence point for several pathological processes rather than a demonstrated driver of any of them. The available evidence neither establishes nor excludes a causal role, and we set out the experiments that would decide.