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
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands.
Department of Molecular Genetics, Erasmus Medical Center, 3015 Rotterdam, the Netherlands; Ri.Med Foundation, 90133 Palermo, Italy.
Cell Rep. 2016 May 31;15(9):1866-75. doi: 10.1016/j.celrep.2016.04.071. Epub 2016 May 19.
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.
帕金森病（PD）的病因病理学与其主要风险因素——衰老之间的潜在关系在很大程度上尚不清楚。鉴于基因组稳定性与衰老之间的因果联系，我们通过评估实验动物模型和人类中与衰老相关的DNA修复途径，研究DNA损伤积累、衰老和PD之间可能存在的联系。我们证明，PD患者的皮肤成纤维细胞表现出有缺陷的核苷酸切除修复（NER）能力，并且NER轻度受损的Ercc1突变小鼠表现出典型的PD样病理改变，包括纹状体多巴胺能神经支配减少、磷酸化α-突触核蛋白水平升高以及线粒体呼吸缺陷。Ercc1小鼠突变体对典型的PD毒素MPTP也更敏感，并且它们的转录组图谱与PD患者的转录组图谱有重要的相似之处。我们的结果表明，DNA修复中的特定缺陷会影响多巴胺能系统，并与人类PD病理学相关，因此可能构成PD的一个与年龄相关的风险因素。
