Fig. 7

Regional timelines of synucleinopathy, neuroinflammation, and degeneration in the substantia nigra and agranular insular cortex following intrastriatal α-syn PFF injection. (Left): Early accumulation of phosphorylated inclusions of α-syn (peak at 2 months) in the substantia nigra leads to loss of TH phenotype and eventual loss of nigrostriatal dopamine neurons by 5–6 months p.i. In the SN, the pattern of microgliosis similarly follows that of pSyn: microglia in the adjacent SNr exhibit a reactive morphology at 2 months p.i. when nearby SNc neurons possess the greatest number of SNc pSyn inclusions. Interestingly, MHC-IIir antigen-presenting microglia in the SNc also peak at 2 months p.i., again coinciding with the greatest number of pSyn intraneuronal inclusions and decrease over time to near non-detectable levels during the interval of degeneration, suggesting a relationship between pathological α-syn and inflammation. (Right): Early accumulation of pSyn inclusions occurs between 2 and 4 months, with inclusions primarily localized to the somata at 2 months, an increase in neuritic inclusions at 4 months, and an observable decrease of overall pSyn pathology at 6 months, suggesting that similar to the SN, neurons in the agranular insular cortex harboring inclusions eventually die off. MHC-II immunoreactivity follows a similar pattern to that observed in the SN, with peak expression observed at 2 months p.i., and decreased over the course of 6 months