The Effect And Mechanism Of Nuclear Localization Alpha-synuclein On Hippocampal Function

Alpha-synuclein(α-syn)is an abundant neuronal protein that is primarily involved in the maintenance of normal synaptic function and the transport of synaptic vesicles.Genetics and neuropathological studies have shown that α-syn is closely associated with Parkinson’s disease(PD)and other neurodegenerative diseases.Numerous studies have shown that α-syn widely exists in the nucleus and can interact with DNA,changing the physicochemical properties of DNA,thereby affecting genomic stability and transcriptional homeostasis.Meanwhile,excessive nuclear translocation of α-syn promotes phosphorylation at Ser129 and changes the level of PD-related genes,which further suggests that excessive nuclear translocation of α-syn is closely related to the pathogenesis of PD.In addition,α-syn dysfunction can impair hippocampal neurogenesis and lead to hippocampal dendritic spine lesions.Cell damage driven by α-syn pathology in the hippocampus may be the potential cause of memory impairment in PD patients.To explore the effect of nuclear translocation of α-syn on hippocampal function,we established the mouse model with different subcellular localizations of α-syn in the hippocampus by injecting rAAV2/9 carrying EGFP,EGFP-SNCA,EGFP-SNCA-NLS,and EGFP-SNCA-NES,and performed behavioral tests at 1 month,3 months,and 6 months,respectively.The results showed that overexpression of α-syn could cause memory impairment,motor dysfunction and anxiety-like behaviors in mice,and the cognitive learning ability and motor ability gradually worsened over time.The behavioral disorders caused by nuclear localized α-syn were more severe than those caused by overexpression of α-syn and nuclear exported α-syn at all times.It was found that nuclear localization α-syn could be phosphorylated in hippocampal nucleus and form numerous aggregates,which can quickly cause DNA damage.And the hippocampal neurons with initial DNA damage attempted to repair DNA damage by activating the G1/S phase cell cycle checkpoint,leading to neuronal cell cycle re-entry.However,the nerve cells are blocked before the G2 phase,which cannot successfully complete the cell cycle and are eventually eliminated through the apoptosis pathway.The nuclear localization of α-syn still maintained the DNA damage response at 3 and 6 months,but it did not activate cell cycle re-entry,so the DNA damaged neurons were eliminated by mediated apoptosis.Subsequently,nuclear localization of α-syn and cell damage signals could activate microglia,releasing large amounts of pro-inflammatory factors and stimulating astrocyte proliferation,induce severe inflammatory response in the hippocampus of mice,and lead to a reduction in the secretion of neurotrophic factors,leading to the exhaustion of the neural stem cell pool and the decline of neurogenesis.At the same time,inflammatory response further aggravates DNA damage,forming a vicious circle that eventually leads to hippocampal dysfunction and impaired cognitive learning and motor abilities.Nuclear translocation of α-syn could increase the expression of c-fos in hippocampal neurons,and induced apoptosis of hippocampal cells.To compensate for the loss of neurons,the activity of hippocampal neurons increases significantly,and excessive release of gamma-aminobutyric acid(GABA)ergic neurotransmitters inhibits glutamatergic nerve transport,resulting in anxise-like behavior.Interestingly,rAAV2/9 viruses injected in the mouse hippocampus could be specifically delivered to the amygdala region and cause pathological accumulation of α-syn,glial cell proliferation,and interneuronal deficits,ultimately affecting anxiety-like behaviors in mice as well.In summary,this study found that overexpression of α-syn in hippocampal nucleus can cause hippocampal dysfunction through DNA damage response,participating in cell cycle regulation,mediating apoptotic pathway,inducing inflammatory response,and leading to hippocampal neurogenesis decline and other processes.At the same time,nuclear localization of α-syn affects hippocampal neuronal excitability and participates in the regulation of GABA functional system,which affects normal hippocampal function and induces cognitive learning impairment,motor dysfunction and anxiety-like behavior in mice.These results suggest that excessive nuclear translocation of α-syn in hippocampal neurons may be a major cause of cognitive decline in PD patients,providing experimental data to support the investigation of the pathogenesis of Parkinson’s disease Dementia(PDD)and providing new ideas for the selection of therapeutic drugs for clinical research.