Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression

AbstractAging 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 the Parkinson’s Progression Markers Initiative cohort to investigate the involvement of DNA damage in PD. Our findings revealed that PD patients exhibit disrupted DNA repair pathways and biased suppression of longer transcripts, indicating the presence of age-related, transcription-stalling DNA damage. Notably, this DNA damage signature was only detected in patients with more severe motor symptom progression over a three-year period, suggesting its potential as a predictor of disease severity. We further validated this signature in independent PD cohorts and confirmed increased signs of DNA damage in dopamine neurons of the substantia nigra pars compacta through histopathological analysis of PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies markers of disease progression providing a readily applicable diagnostic platform to prognosticate disease progression.One Sentence SummaryParkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression.