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

The authors have declared no competing interest.

This study was supported by the Michael J Fox Foundation (Pier Giorgio Mastroberardino and Jan Vijg). Daisy Sproviero was supported by Fondazione Veronesi.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Parkinson's Progression Markers Initiative (PPMI) is an observational, international, multicenter study and the dataset is available after request on the website described below. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines after approval of local ethics committees of the participating sites as described in https://www.michaeljfox.org/news/ppmi-rna-sequencing-project. Written informed consent was obtained from all participants before undergoing any study evaluations. Formalin fixed paraffin embedded fully anonymous human midbrain tissue sections derived from PD patients and age-matched healthy controls were kindly provided by the Queen Square Brain Bank for Neurological Disorders, London, UK according to Material transfer agreement number 10-2019. The Ethics Committee made up by Prof. Marco Pedrazzi, Prof.ssa Francesca Caloni, Prof.ssa Monica Ferraroni, Prof. Carlo Flamigni, Prof. Fabrizio Gardoni, Prof.ssa Daniela Milani, Prof. Emanuele Montanari, Prof. Gianfranco Mormino, Prof.ssa Francesca Poggi, Prof. Giuseppe Testa, Prof. Giovanni Ziccardi (all affiliated to Universita degli Studi di Milano Statale, Milan, Italy) examined the research project, Neurodegenerative proteinopathies: mechanical stress and nuclear deformation, presented by Dr. Domenico Delia, co-author on the manuscript, who also performed the experiments. The Ethics Committee during the session on 23rd September 2019, considered the received proposal valid, adequately documented, as well as in line with ethical standards. All the informations are described in document Allegato 4 (Protocol n-39-19).

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