Inefficient DNA repair is an aging-related modifier of parkinson's disease

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-relat...

Full description

Autores:
Tipo de recurso:
Fecha de publicación:
2016
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/18940
Acceso en línea:
http://repository.urosario.edu.co/handle/10336/18940
Palabra clave:
Alpha Synuclein
Cre Recombinase
Excision Repair Cross Complementing Protein 1
Histone H2Ax
Histone H2Ax Gamma
Unclassified Drug
Dna Binding Protein
Endonuclease
Aging
Animal Experiment
Animal Model
Autonomic Innervation
Controlled Study
Disease Association
Dna Damage
Dna Repair
Dopaminergic System
Double Stranded Dna Break
Down Regulation
Enzyme Activity
Ercc1 Gene
Excision Repair
Gene Expression
Gene Mutation
Human
Human Cell
Mitochondrial Respiration
Mouse
Neuropathology
Nonhuman
Oxidation Reduction State
Parkinson Disease
Priority Journal
Protein Expression
Protein Homeostasis
Protein Phosphorylation
Rna Sequence
Skin Fibroblast
Upregulation
Aging
Animal
Corpus Striatum
Dopaminergic Nerve Cell
Fibroblast
Metabolism
Parkinson Disease
Pathology
Ultrastructure
Aging
Animals
Corpus Striatum
Dna Repair
Dna-Binding Proteins
Dopaminergic Neurons
Endonucleases
Fibroblasts
Mice
Parkinson Disease
Enfermedades
Mouse
Ercc1 Protein
Article
Humans
Enfermedad de parkinson
Edad adulta
Vejez
Rights
License
Abierto (Texto Completo)
Description
Summary: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. © 2016 The Author(s).