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

被引：90

作者：

Sepe, Sara ^{[1
]}

Milanese, Chiara ^{[1
,2
]}

Gabriels, Sylvia ^{[1
]}

Derks, Kasper W. J. ^{[1
]}

Payan-Gomez, Cesar ^{[1
,3
]}

van IJcken, Wilfred F. J. ^{[4
]}

Rijksen, Yvonne M. A. ^{[1
]}

Nigg, Alex L. ^{[5
]}

Moreno, Sandra ^{[6
]}

Cerri, Silvia ^{[7
]}

Blandini, Fabio ^{[7
]}

Hoeijmakers, Jan H. J. ^{[1
]}

Mastroberardino, Pier G. ^{[1
]}

机构：

[1] Erasmus MC, Dept Mol Genet, NL-3015 Rotterdam, Netherlands

[2] Ri Med Fdn, I-90133 Palermo, Italy

[3] Univ Rosario, Fac Ciencias Nat & Matemat, Bogota 111711, Colombia

[4] Erasmus MC, Ctr Biom, NL-3015 Rotterdam, Netherlands

[5] Erasmus MC, Opt Imaging Ctr, NL-3015 Rotterdam, Netherlands

[6] Univ Rome Tre, I-00146 Rome, Italy

[7] C Mondino Natl Neurol Inst, Ctr Res Neurodegenerat Dis, Lab Funct Neurochem, I-27100 Pavia, Italy

来源：

CELL REPORTS | 2016年 / 15卷 / 09期

基金：

欧盟第七框架计划; 欧洲研究理事会;

关键词：

NUCLEOTIDE EXCISION-REPAIR; LEWY BODY DISEASE; DOPAMINERGIC-NEURONS; SUBSTANTIA-NIGRA; DAMAGE; SENESCENCE; STRESS; SYSTEM; CELLS;

D O I：

10.1016/j.celrep.2016.04.071

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1866 / 1875

页数：10

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