Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion.

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 alpha-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of alpha-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and alpha-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 alpha-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 alpha-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 alpha-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes alpha-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and alpha-synuclein, and identify TFEB as not only a potential target for preventing alpha-synuclein transmission, but also a critical factor for iron-induced alpha-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 alpha-synuclein transmission in Parkinson's disease.