Nuclear Alpha-Synuclein: Mechanisms and Implications for Synucleinopathies.

Alpha-synuclein (aSyn), historically studied for its synaptic functions and central role in Lewy body pathology, is emerging as a protein with significant nuclear activities relevant to Parkinson's disease (PD) and related synucleinopathies. Recent advances reveal that aSyn dynamically localizes to neuronal nuclei in both health and disease, where its interactions with chromatin and DNA may contribute to the regulation of genomic stability, DNA damage responses, and cellular aging. Studies using experimental models demonstrate that nuclear aSyn promotes neurodegeneration through transcriptional dysregulation, DNA repair deficits, and cellular senescence, especially when present in phosphorylated or oligomeric forms. The detection of nuclear aSyn in human tissues has proven challenging, but improvements in immunohistochemical and molecular techniques now allow deeper exploration of its physiological and pathological states. Mechanistic studies indicate that aSyn can modulate nuclear import pathways and directly interact with genomic repair machinery, suggesting new avenues for disease modification. As such, nuclear aSyn represents both a promising biomarker for disease stratification and a potential therapeutic target. Integrating mechanistic, biomarker, and translational research on nuclear aSyn may transform our understanding of PD progression and enable precision medicine approaches for early diagnosis and intervention in synucleinopathies. © 2025 International Parkinson and Movement Disorder Society.