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

Abstract

SummaryThe 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.

High Pressure-Induced mtDNA Alterations in Retinal Ganglion Cells and Subsequent Apoptosis

“…In addition, the compromise of the mtDNA repair system can also result in mtDNA alterations (Francisconi et al, 2006; Ciccone et al, 2013; Venesio et al, 2013; Sepe et al, 2016). OGG1, MYH and POLG are important mtDNA repair/replication enzymes.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Oxidative damage, dysregulated neuronal Ca 2+ homeostasis, impaired DNA repair, impaired adaptive cellular stress responses, aberrant neuronal network activity, and neuroinflammation all occur in affected brain regions during the course of PD, and each of these age-related alterations increases the vulnerability of neurons to α-synuclein pathology, and mitochondrial and autophagy dysfunction (Olanow et al, 2015; Ransohoff, 2016; Sepe et al, 2016; Jahanshahi and Rothwell, 2017; Menzies et al, 2017; Surmeier et al, 2017a). Conversely, aggregating α-synuclein and mitochondrial dysfunction exacerbate oxidative stress and DNA damage, destabilize neuronal Ca 2+ homeostasis, and promote neuroinflammation (Schapira et al, 2014).…”

Analysis of mtDNA/nDNA Ratio in Mice

“…In humans, defects in mtDNA maintenance generated by mutations in genes involved in mtDNA replication and nucleotide biosynthesis cause mtDNA depletion syndromes (MDS) (El-Hattab and Scaglia, 2013). Such mtDNA depletions are also associated with metabolic diseases, including type 2 diabetes, cancers and neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Machado-Joseph disease (Abolhassani et al, 2016; Kazachkova et al, 2013; Ramos et al, 2015; Sepe et al, 2016). During aging, mtDNA copy number also decreases, probably because it is prone to oxidative damage by reactive oxygen species (ROS) produced in the mitochondrial matrix.…”