Nuclear Alpha-Synuclein: Mechanisms and Implications for Synucleinopathies

TY - JOUR

T1 - Nuclear Alpha-Synuclein

T2 - Mechanisms and Implications for Synucleinopathies

AU - Outeiro, Tiago Fleming

AU - Koss, David J.

N1 - Copyright: © 2025 International Parkinson and Movement Disorder Society.

PY - 2025/11/26

Y1 - 2025/11/26

N2 - 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.

AB - 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.

KW - alpha-synuclein

KW - DNA damage

KW - neurodegeneration

KW - Parkinson's disease

KW - protein aggregation

UR - https://www.scopus.com/pages/publications/105023202411

U2 - 10.1002/mds.70138

DO - 10.1002/mds.70138

M3 - Article

C2 - 41293789

AN - SCOPUS:105023202411

SN - 0885-3185

JO - Movement Disorders

JF - Movement Disorders

ER -