In this study, we conducted a clinical analysis of lymphocyte subtypes in 268 patients with Parkinson's disease (PD) to assess their clinical impact as a potential marker of advanced PD in Chinese patients. The participants comprised 268 sporadic PD patients and 268 healthy controls. The numbers of natural killer (NK) cells and CD3+, CD3+CD4+, CD3+CD8+, and CD19+ lymphocytes from peripheral blood were determined by immunostaining and flow cytometric analysis and the percentages of these CD+ T cells were calculated. The ratio of regulatory T (Treg)/helper T 17 (Th17) lymphocytes from 64 PD patients and 46 controls was determined by flow cytometric analysis. The results showed that the percentage of NK cells was higher in advanced PD patients than in controls (22.92% ± 10.08% versus 19.76% ± 10.09%, P = 0.006), while CD3+ T cells are decreased (62.93% ± 9.27% versus 65.75% ± 9.13%, P = 0.005). The percentage of CD19+ B cells in male patients was lower (P = 0.021) than in female patients, whereas NK cells were increased (P < 0.0001). The scores on the Unified Parkinson's Disease Rating Scale (UPDRS) and the Non-Motor Symptoms Scale in late-onset PD patients were significantly higher than those in early-onset patients (P = 0.024 and P = 0.007, respectively). The percentage of CD19+ B cells in patients with UPDRS scores >24 was lower than in those with scores <24 (10.17% ± 4.19% versus 12.22% ± 5.39%, P = 0.009). In addition, the Treg/Th17 ratio in female patients was higher than that in female controls (13.88 ± 6.32 versus 9.94 ± 4.06, P = 0.042). These results suggest that the percentages of NK cells, CD3+ T cells, and CD19+ B cells along with the Treg/Th17 ratio in peripheral blood may be used to predict the risk of PD in Chinese individuals and provide fresh avenues for novel diagnostic biomarkers and therapeutic designs.

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Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.

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