Defective DNA repair has been linked with age-associated neurodegenerative disorders. Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Whether damages to nuclear DNA contribute to neurodegeneration of PD still remain obscure. in this study we aim to explore whether nuclear DNA damage induce dopamine neuron degeneration in A53T human a-Synuclein over expressed mouse model. We investigated the effects of X-ray irradiation on A53T-alpha-Syn MEFs and A53T-alpha-Syn transgene mice. Our results indicate that A53T-alpha-Syn MEFs show a prolonged DNA damage repair process and senescense phenotype. DNA damage preceded onset of motor phenotype in A53T-beta-Syn transgenic mice and decrease the number of nigrostriatal dopaminergic neurons. Neurons of A53T-alpha-Syn transgenic mice are more fragile to DNA damages. (C) 2016 Elsevier Inc. All rights reserved.