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Cell Rep. 2016 May 31;15(9):1866-75. doi: 10.1016/j.celrep.2016.04.071. Epub 2016 May 19.

Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease.

Author information

1
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
2
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands; Ri.Med Foundation, 90133 Palermo, Italy.
3
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands; Facultad de Ciencias Naturales y Matemáticas, Universidad del Rosario, 111711 Bogotá, Colombia.
4
Center for Biomics, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands.
5
Optical Imaging Center, Erasmus Medical Centre, 3015 Rotterdam, the Netherlands.
6
University of "Roma Tre," 00146 Rome, Italy.
7
Laboratory of Functional Neurochemistry, Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, 27100 Pavia, Italy.
8
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands. Electronic address: p.g.mastroberardino@erasmusmc.nl.

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.

PMID:
27210754
PMCID:
PMC4893155
DOI:
10.1016/j.celrep.2016.04.071
[Indexed for MEDLINE]
Free PMC Article

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