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

Daisy Sproviero; Cesar Payan Gomez; Chiara Milanese; Shixiang Sun; Akos Gyenis; Domenico Delia; Tammaryn Lashley; Jan Vijg; Jan Hoeijmakers; Pier Mastroberardino

doi:10.1101/2024.03.25.24301713

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

Daisy Sproviero
, Cesar Payan Gomez
, Chiara Milanese
, Shixiang Sun
, Akos Gyenis
, Domenico Delia
, Tammaryn Lashley
, Jan Vijg
, Jan Hoeijmakers
, Pier Mastroberardino^*

^*Corresponding author for this work

Molecular Genetics

FIRC Institute of Molecular Oncology
Universidad Nacional de Colombia
IFOM ETS - The AIRC Institute of Molecular Oncology
Albert Einstein College of Medicine
University of Cologne
Albert Einstein College of Medicine of Yeshiva University
Shanghai Jiao Tong University
Unit Healthy Living
INGENY B.V.
Beth Israel Deaconess Medical Center
Princess Máxima Center for Pediatric Oncology
Università degli Studi dell’Aquila

Research output: Contribution to journal › Article › Academic

Abstract

Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how agerelated 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 agerelated, 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.

Original language	English
Pages (from-to)	1-34
Number of pages	34
Journal	medRxiv : the preprint server for health sciences
DOIs	https://doi.org/10.1101/2024.03.25.24301713
Publication status	Published - 26 Mar 2024

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abstract = "Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how agerelated 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 agerelated, 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.",

author = "Daisy Sproviero and \{Payan Gomez\}, Cesar and Chiara Milanese and Shixiang Sun and Akos Gyenis and Domenico Delia and Tammaryn Lashley and Jan Vijg and Jan Hoeijmakers and Pier Mastroberardino",

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T1 - Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression

AU - Sproviero, Daisy

AU - Payan Gomez, Cesar

AU - Milanese, Chiara

AU - Sun, Shixiang

AU - Gyenis, Akos

AU - Delia, Domenico

AU - Lashley, Tammaryn

AU - Vijg, Jan

AU - Hoeijmakers, Jan

AU - Mastroberardino, Pier

PY - 2024/3/26

Y1 - 2024/3/26

N2 - Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how agerelated 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 agerelated, 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.

AB - Aging is the main risk factor for Parkinson's disease (PD), yet our understanding of how agerelated 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 agerelated, 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.

U2 - 10.1101/2024.03.25.24301713

DO - 10.1101/2024.03.25.24301713

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JO - medRxiv : the preprint server for health sciences

JF - medRxiv : the preprint server for health sciences

ER -

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

Abstract

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