RNA Granules at the Crossroads of Synaptic Dysfunction and Neurodegeneration

RNA granules are dynamic, membraneless organelles essential for the spatial and temporal regulation of mRNA metabolism, particularly in neurons, where local protein synthesis supports synaptic plasticity and function. This review explores the diverse types of RNA granules (e.g., transport granules, stress granules, and processing bodies), their formation mechanisms, molecular composition, and relevance to synaptic physiology. We focus on the central role of RNA-binding proteins (RBPs) in orchestrating granule dynamics and their fine-tuning of synaptic responses under both physiological and stress conditions. Mounting evidence implicates the dysfunction of RNA granules in neurodegenerative diseases. Altered phase separation, RBP aggregation, and persistent stress granules contribute to the formation of pathological RNA granules that interfere with local translation and synaptic maintenance. Key RBPs, including TDP-43, FUS, and TIA-1, are frequently misregulated in disease contexts. Furthermore, Tau is a multifunctional protein traditionally associated with microtubule stabilization but is increasingly recognized for its role in the translational stress response, which includes RBP mislocalization and RNA granule disruption. We examine how chronic stress can exacerbate these mechanisms, acting as an environmental trigger of synaptic vulnerability associated with neurodegeneration. In summary, we explore a conceptual framework connecting RNA granule dysregulation, Tau pathology, and local translation disruption, three processes that converge on synaptic impairment, a central feature of many neurodegenerative diseases characterized by abnormal Tau. Investigating this triad presents a promising avenue for understanding disease mechanisms and identifying novel therapeutic targets that aim to restore RNA metabolism, prevent toxic Tau interactions, and preserve synaptic health.