Nuclear localization of alpha-synuclein affects the cognitive and motor behavior of mice by inducing DNA damage and abnormal cell cycle of hippocampal neurons

Nuclear accumulation of alpha-synuclein (alpha-syn) in neurons can promote neurotoxicity, which is considered the key factor in the pathogenesis of synucleinopathy. The damage to hippocampus neurons driven by alpha-syn pathology is also the potential cause of memory impairment in Parkinson's disease (PD) patients. In this study, we examined the role of alpha-syn nuclear translocation in the cognition and motor ability of mice by overexpressing alpha-syn in cell nuclei in the hippocampus. The results showed that the overexpression of alpha-syn in nuclei was able to cause significant pathological accumulation of alpha-syn in the hippocampus, and quickly lead to memory and motor impairments in mice. It might be that nuclear overexpression of alpha-syn may cause DNA damage of hippocampal neurons, thereby leading to activation and abnormal blocking of cell cycle, and further inducing apoptosis of hippocampal neurons and inflammatory reaction. Meanwhile, the inflammatory reaction further aggravated DNA damage and formed a vicious circle. Therefore, the excessive nuclear translocation of alpha-syn in hippocampal neurons may be one of the main reasons for cognitive decline in mice.

Automated summary

Excessive nuclear translocation of alpha-syn in hippocampal neurons can lead to pathological accumulation, resulting in memory and motor impairments.