Decoding the Role of Familial Parkinson’s Disease-Related Genes in DNA Damage and Repair

DNA Damage-Mediated Neurotoxicity in Parkinson’s Disease

“…In fact, evidence of DNA damage in PD was reported several decades ago [ 14 ]. Compared with healthy controls, the level of 8-OHdG, a marker of oxidative DNA damage, was significantly upregulated in the DA neurons of PD patients [ 26 ].…”

“…It has to be mentioned that mutations in several genes encoding key proteins involved in DNA repair have been shown to contribute to the progression of PD [ 14 ]. For instance, mice lacking the DNA repair protein ATM exhibited PD-like motor abnormalities, accompanied by reduced expression of tyrosine hydroxylase (TH) and the dopamine transporter (DAT), as well as α-synuclein-positive inclusions [ 21 , 47 ].…”

“…Unlike other age-related neurodegenerative diseases, many DNA repair proteins are upregulated in the brains of PD patients and animal models, which is partially explained by DNA damage-induced repair activation [ 15 , 75 ]. Conversely, a growing body of studies suggests that DNA repair is defective in PD [ 14 , 15 ]. For example, the ability of NER was significantly reduced in skin fibroblasts isolated from patients with PD [ 23 ].…”

“…Evidence for a causal contribution of DNA damage in the onset and progression of neurodegenerative diseases comes from rare patients and model organisms with mutations in DNA damage-responsive genes [ 10 , 11 ]. Interestingly, increasing evidence suggests that DNA damage and repair deficiency are also implicated in age-related neurodegenerative diseases, such as AD (Alzheimer’s disease), PD, ALS (Amyotrophic lateral sclerosis), and Huntington’s disease (HD) [ 12 , 13 , 14 , 15 , 16 , 17 ]. In PD, the pathogenicity of DNA damage is not only enhanced by its association with typical PD pathology, but also by the fact that DNA damage accumulation occurs before the onset of PD, implying its direct involvement in the pathophysiology [ 18 , 19 , 20 ].…”

“…In PD, the pathogenicity of DNA damage is not only enhanced by its association with typical PD pathology, but also by the fact that DNA damage accumulation occurs before the onset of PD, implying its direct involvement in the pathophysiology [ 18 , 19 , 20 ]. More importantly, the loss of function of specific DNA repair proteins in mice can recapitulate part of the disease phenotype of PD, and some proteins known to play key roles in PD have been shown to directly mediate DNA repair [ 14 , 21 , 22 , 23 , 24 , 25 ]. All this evidence suggests that DNA damage may be the direct mechanism of neurodegeneration in PD.…”