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

Abstract

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.

Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

“…Our results show the therapeutic potential of the novel iron chelators, where it is well established that α-SYN aggregation, as seen in PD brains, can be promoted by excess iron (Xiao et al 2018). The central role that iron plays in LB promotion was further underlined by work reporting iron co-localization within LBs in the brains of PD patients (Castellani et al 2000).…”

Interaction of α-synuclein and Parkin in iron toxicity on SH-SY5Y cells: implications in the pathogenesis of Parkinson's disease

“…The interactions of iron and α-synuclein have been extensively studied, and iron has been shown to bind to α-synuclein and promote the aggregation of α-synuclein [38]. Furthermore, iron has been shown to increase the translation of α-synuclein mRNA and facilitate the secretion and cell-to-cell transmission of α-synuclein by inhibiting the fusion of autophagosome and lysosome [39]. However, our results tend to suggest another mechanism of iron-induced enhancement of α-synuclein accumulation in neural cells through inactivation of ubiquitin E3 ligase activity of Parkin leading to decreased proteasomal degradation of α-synuclein.…”

Lysosome biogenesis in health and disease

“…Iron indeed accumulates in various neurodegenerative disorders and particularly in synucleinopathies (Snyder and Connor ), where it contributes to α‐synuclein aggregation and transmission by interfering with TFEB function via activation of the Akt/mTORC1 axis (Xiao et al . ).…”