Decoding the functions of nuclear speckles in neurodegeneration

Nuclear speckles, traditionally considered mainly as reservoirs of splicing factors, are increasingly recognized as dynamic biomolecular condensates essential for RNA metabolism, transcriptional regulation, and chromatin organization. Recent advances reveal their phase separation properties, compositional complexity, and stress-responsive remodeling, positioning nuclear speckles as key regulators of proteostasis and stress adaptation. Here, we synthesize emerging evidence linking nuclear speckle dysfunction to neurodegenerative proteinopathies, particularly amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and tauopathies. We highlight how disease-associated repeat RNAs, dipeptide repeat proteins, and hyperphosphorylated tau disrupt nuclear speckle integrity, driving transcriptional and splicing defects. Finally, we discuss therapeutic strategies to rejuvenate nuclear speckles, emphasizing their potential as novel targets for restoring proteostasis and mitigating neurodegeneration. This review underscores nuclear speckles as critical yet underexplored regulators of neuronal resilience.