Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson’s Disease
Sara Sepe,
Chiara Milanese,
Sylvia Gabriels,
Kasper W.J. Derks,
Cesar Payan-Gomez,
Wilfred F.J. van IJcken,
Yvonne M.A. Rijksen,
Alex L. Nigg,
Sandra Moreno,
Silvia Cerri,
Fabio Blandini,
Jan H.J. Hoeijmakers,
Pier G. Mastroberardino
Affiliations
Sara Sepe
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Chiara Milanese
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Sylvia Gabriels
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Kasper W.J. Derks
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Cesar Payan-Gomez
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Wilfred F.J. van IJcken
Center for Biomics, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands
Yvonne M.A. Rijksen
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Alex L. Nigg
Optical Imaging Center, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands
Sandra Moreno
University of “Roma Tre,” 00146 Rome, Italy
Silvia Cerri
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, 27100 Pavia, Italy
Fabio Blandini
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, 27100 Pavia, Italy
Jan H.J. Hoeijmakers
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
Pier G. Mastroberardino
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands
The underlying relation between Parkinson’s disease (PD) etiopathology and its major risk factor, aging, is largely unknown. In light of the causative link between genome stability and aging, we investigate a possible nexus between DNA damage accumulation, aging, and PD by assessing aging-related DNA repair pathways in laboratory animal models and humans. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that Ercc1 mutant mice with mildly compromised NER exhibit typical PD-like pathological alterations, including decreased striatal dopaminergic innervation, increased phospho-synuclein levels, and defects in mitochondrial respiration. Ercc1 mouse mutants are also more sensitive to the prototypical PD toxin MPTP, and their transcriptomic landscape shares important similarities with that of PD patients. Our results demonstrate that specific defects in DNA repair impact the dopaminergic system and are associated with human PD pathology and might therefore constitute an age-related risk factor for PD.
