Senescence and impaired DNA damage responses in alpha-synucleinopathy models

α-Synuclein is a crucial element in the pathogenesis of Parkinson’s disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD. Neurodegeneration: Parkinson’s protein impairs DNA repair capacity Excess levels of a protein involved in Parkinson’s disease can impair the brain’s capacity to repair DNA damage, leading to a state of cellular aging that accelerates neuronal death. When aggregated, the α-synuclein protein plays a major role in Parkinson’s disease and other neurodegenerative disorders. A team from South Korea, led by He-Jin Lee of Konkuk University, Seoul, and Seung-Jae Lee of Seoul National University College of Medicine, showed that human neuronal cells and mouse models with elevated expression of α-synuclein develop double-stranded breaks in their genomes as a consequence of deficient quality control mechanisms. The accumulated DNA damage spurs the cells to enter a state in which they show canonical signs of cellular aging but remain metabolically active in ways that fuel neurodegeneration. Therapies that target these processes could help prevent or treat α-synuclein–linked diseases.