Nuclear RNA clusters are dynamic structural entities in Huntington's disease.

Huntington's disease research has focused on either loss of normal huntingtin function or toxic gain-of-function of the mutant huntingtin protein as a key driver of pathology. The role of mutant HTT mRNA in vivo has been only partially studied and remains largely unexplored. Recently, we discovered that full-length 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 present at the prenatal stage, indicating early developmental effects. Moreover, these clusters were confined to neurons, implying a neuron-specific mechanism of accumulation, and were colocalised with core spliceosomal proteins, suggesting an 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 importance of HTT mRNA accessibility to therapeutic interventions and may guide future design of HTT-targeting therapies.