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

Resultado de la investigación: Contribución a RevistaArtículo

15 Citas (Scopus)

Resumen

© 2016 The Author(s).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.
Idioma originalEnglish (US)
Páginas (desde-hasta)1866-1875
Número de páginas10
PublicaciónCell Reports
DOI
EstadoPublished - may 31 2016

Huella dactilar

DNA Repair
Parkinson Disease
Repair
Aging of materials
DNA
Nucleotides
Synucleins
Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Defects
Genomic Instability
Pathology
Fibroblasts
DNA Damage
Respiration
Animals
Animal Models
Genes
Skin

Citar esto

Sepe, S., Milanese, C., Gabriels, S., Derks, K. W. J., Payan-Gomez, C., van IJcken, W. F. J., ... Mastroberardino, P. G. (2016). Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. Cell Reports, 1866-1875. https://doi.org/10.1016/j.celrep.2016.04.071
Sepe, Sara ; Milanese, Chiara ; Gabriels, Sylvia ; Derks, Kasper W J ; Payan-Gomez, Cesar ; van IJcken, Wilfred F J ; Rijksen, Yvonne M A ; Nigg, Alex L. ; Moreno, Sandra ; Cerri, Silvia ; Blandini, Fabio ; Hoeijmakers, Jan H J ; Mastroberardino, Pier G. / Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. En: Cell Reports. 2016 ; pp. 1866-1875.
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abstract = "{\circledC} 2016 The Author(s).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.",
author = "Sara Sepe and Chiara Milanese and Sylvia Gabriels and Derks, {Kasper W J} and Cesar Payan-Gomez and {van IJcken}, {Wilfred F J} and Rijksen, {Yvonne M A} and Nigg, {Alex L.} and Sandra Moreno and Silvia Cerri and Fabio Blandini and Hoeijmakers, {Jan H J} and Mastroberardino, {Pier G.}",
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Sepe, S, Milanese, C, Gabriels, S, Derks, KWJ, Payan-Gomez, C, van IJcken, WFJ, Rijksen, YMA, Nigg, AL, Moreno, S, Cerri, S, Blandini, F, Hoeijmakers, JHJ & Mastroberardino, PG 2016, 'Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease', Cell Reports, pp. 1866-1875. https://doi.org/10.1016/j.celrep.2016.04.071

Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. / Sepe, Sara; Milanese, Chiara; Gabriels, Sylvia; Derks, Kasper W J; Payan-Gomez, Cesar; van IJcken, Wilfred F J; Rijksen, Yvonne M A; Nigg, Alex L.; Moreno, Sandra; Cerri, Silvia; Blandini, Fabio; Hoeijmakers, Jan H J; Mastroberardino, Pier G.

En: Cell Reports, 31.05.2016, p. 1866-1875.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease

AU - Sepe, Sara

AU - Milanese, Chiara

AU - Gabriels, Sylvia

AU - Derks, Kasper W J

AU - Payan-Gomez, Cesar

AU - van IJcken, Wilfred F J

AU - Rijksen, Yvonne M A

AU - Nigg, Alex L.

AU - Moreno, Sandra

AU - Cerri, Silvia

AU - Blandini, Fabio

AU - Hoeijmakers, Jan H J

AU - Mastroberardino, Pier G.

PY - 2016/5/31

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N2 - © 2016 The Author(s).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.

AB - © 2016 The Author(s).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.

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DO - 10.1016/j.celrep.2016.04.071

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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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