Sproviero Daisy, Payán-Gómez César, Milanese Chiara, Barnhoorn Sander, Sun Shixiang, Gyenis Akos, Delia Domenico, Lashley Tammaryn, Hoeijmakers Jan H J, Vijg Jan, Mastroberardino Pier G
IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
Universidad Nacional de Colombia, Sede de La Paz, La Paz, Colombia.
Nat Aging. 2025 Sep 5. doi: 10.1038/s43587-025-00926-x.
Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson's Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression.
衰老为帕金森病（PD）的主要风险因素，然而我们对于与年龄相关的机制如何促成PD病理生理学的了解仍很有限。我们对帕金森病进展标志物计划队列中的血样进行了纵向分析，以研究PD中的DNA损伤。PD患者表现出DNA修复途径紊乱以及对较长转录本的偏向性抑制，表明存在与年龄相关的、转录停滞的DNA损伤。值得注意的是，在初次就诊时，这种DNA损伤特征仅在运动症状在3年内进展更严重的患者中被检测到，这表明其具有作为疾病严重程度预测指标的潜力。我们在独立的PD队列中验证了这一特征，并证实了在死后的PD大脑中，外周血细胞和黑质致密部的多巴胺神经元中的DNA损伤增加。我们的研究揭示了PD发病机制中一种与衰老相关的机制，并确定了疾病进展的潜在标志物，提供了一个预测疾病进展的诊断平台。
