title: Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: Sepe
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands; Ri.Med Foundation, 90133 Palermo, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Milanese
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gabriels
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Kasper W J
authors.initials: KW
authors.lastname: Derks
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands; Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, 111711 Bogotá, Colombia.
authors.forename: Cesar
authors.initials: C
authors.lastname: Payan-Gomez
authors.affiliation: Center for Biomics, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Yvonne M A
authors.initials: YM
authors.lastname: Rijksen
authors.affiliation: Optical Imaging Center, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands.
authors.forename: Alex L
authors.initials: AL
authors.lastname: Nigg
authors.affiliation: University of "Roma Tre," 00146 Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Moreno
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, 27100 Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cerri
authors.affiliation: Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, 27100 Pavia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Blandini
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands. Electronic address: p.g.mastroberardino@erasmusmc.nl.
authors.forename: Pier G
authors.initials: PG
authors.lastname: Mastroberardino
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D003342:Corpus Striatum / Q000473:pathology / Q000648:ultrastructure; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology / Q000648:ultrastructure; D004720:Endonucleases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D010300:Parkinson Disease / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; C499360:Ercc1 protein, mouse