Nuclear RNA Clusters Are Dynamic Structural Entities in Huntington’s Disease

Huntington’s disease research has focused on a toxic protein gain-of-function as the main driver of pathology. The role of mutant HTT mRNA in vivo has been only partially studied and remains largely unexplored. Recently, we discovered that fully processed human HTT mRNA is retained, together with the alternatively processed HTT1a transcript, in RNA nuclear clusters in YAC128 mouse brains. Here, we demonstrate that these clusters were already present in the prenatal stage at day 14.5, indicating early developmental effects. Moreover, these clusters were confined to neurons, implying a neuron-specific mechanism of accumulation, and were colocalised with Prpf8, a core spliceosomal protein, suggesting potential impact on nuclear homeostasis. HTT nuclear RNA clusters showed remarkable dynamics, rapidly dissolving when ionic interactions were disrupted or transcription and splicing were inhibited. This malleability underscores the accessibility of HTT mRNA to therapeutic interventions and may guide the future design of HTT -targeting therapies.