Long-term hyperglycemia aggravatesα-synuclein aggregation and dopaminergic neuronal loss in a Parkinson’s disease mouse model

Background:Growing evidence suggests an association between Parkinson’s disease(PD)and diabetes mellitus(DM).At the cellular level,long-term elevated levels of glucose have been shown to lead to nigrostriatal degeneration in PD models.However,the underlying mechanism is still unclear.Previously,we have elucidated the potential of type 2 diabetes mellitus(T2DM)in facilitating PD progression,involving aggregation of both alpha-synuclein(α-syn)and islet amyloid polypeptide in the pancreatic and brain tissues.However,due to the complicated effect of insulin resistance on PD onset,the actual mechanism of hyperglycemia-induced dopaminergic degeneration remains unknown.Methods:We employed the type 1 diabetes mellitus(T1DM)model induced by streptozotocin(STZ)injection in a transgenic mouse line(BAC-α-syn-GFP)overexpressing humanα-syn,to investigate the direct effect of elevated blood glucose on nigrostriatal degeneration.Results:STZ treatment induced more severe pathological alterations in the pancreatic islets and T1DM symptoms inα-syn-overexpressing mice than in wild-type mice,at one month and three months after STZ injections.Behavioral tests evaluating motor performance confirmed the nigrostriatal degeneration.Furthermore,there was a marked decrease in dopaminergic profiles and an increase ofα-syn accumulation and Serine 129(S129)phosphorylation in STZ-treatedα-syn mice compared with the vehicle-treated mice.In addition,more severe neuroinflammation was observed in the brains of the STZ-treatedα-syn mice.Conclusion:Our results solidify the potential link between DM and PD,providing insights into how hyperglycemia induces nigrostriatal degeneration and contributes to pathogenic mechanisms in PD.