Background: The mechanisms underlying the pathogenesis and progression of Parkinson’s disease (PD) remain elusive, but recent opinions and perspectives have focused on whether the inflammation process induced by microglia contributes to α-synuclein-mediated toxicity. Migration of microglia to the substantia nigra (SN) could precede neurodegeneration inA53Tmice. We hypothesized that CXCL12 could be a mediator in the α-synuclein-induced migration of microglia.Methods: After establishing appropriate animal and cell culture models, we explored the relationship between α-synuclein and CXCL12 inA53Tmice, primary microglia, and BV-2 cell lines. We also explored the mechanisms of these interactions and the signaling processes involved in neuroinflammation.Results: We confirmed the positive correlation between α-synuclein and CXCL12 in the postmortem brain tissue of PD patients and the upregulated CXCR4 expression in SN microglia ofA53Tmice. In addition, as expected, α-synuclein increased the production of CXCL12 in microglia via TLR4/IκB-α/NF-κB signaling. Importantly, CXCL12/CXCR4/FAK/Src/Rac1 signaling was shown to be involved in α-synuclein-induced microglial accumulation.Conclusions: Our study suggests that CXCL12 could be a novel target for the prevention of α-synuclein-triggered ongoing microglial responses. Blocking CXCL12/CXCR4 may be a potential therapeutic approach for PD progression.

Background: Inflammations play crucial role in the pathogenesis of Parkinson’s disease (PD), however, their possible value in the diagnosis or tracking of the progress of PD is still limited, because of discordant results in the literature and a lack of information regarding its reproducibility. Thus, overall longitudinal and cross-sectional studies are needed. This multicentre study was designed to investigate the association between multiple peripheral immune biomarkers and the development and progression of PD. Methods: This was a longitudinal and multicentre study. First, we measured the levels of five typical cytokines and five focused chemokines in 76 PD patients and 76 healthy controls (HCs) in a discovery cohort. Then, a validation cohort of 80 PD and 80 HC participants was recruited from four multicentre locations. In addition, a prospective follow-up of early-stage PD patients was performed with significant biomarkers. Finally, we performed further verification in an exploratory set of patients with idiopathic REM sleep behaviour disorder (iRBD). Results: In the discovery set, CXCL12, CX3CL1 and IL-8 levels were significantly higher in PD patients than in HCs (p < 0.05). The receiver-operating characteristic (ROC) curve for a combination of these three biomarkers produced a high area under the curve (AUC) of 0.89 (p < 0.001). Moreover, four biomarkers (the previous three and CCL15) were significantly associated with PD in the discovery and validation cohorts. Furthermore, in the prospective follow-up cohort, CX3CL1 levels were associated with motor progression after a mean interval of 43 months. In addition, CX3CL1 and IL-8 levels were higher in iRBD patients than in HCs. Conclusion: We showed a correlation between a profile of four peripheral immune biomarkers and PD development and progression. Our findings may provide a basis whereby PD patients with abnormal inflammatory profiles can be identified and receive timely therapeutic interventions.

D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late‐onset, autosomal dominant familial Parkinson's disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD‐related deficits in vivo remains unclear. In the present study, we thoroughly characterized the biochemical, pathological, and behavioral changes of a VPS35 D620N knockin (KI) mouse model with chronic aging. We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age‐dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α‐synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35‐DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP‐mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins. Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α‐synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation‐associated PD in vivo.