期刊
NEUROCHEMICAL RESEARCH
卷 46, 期 6, 页码 1502-1513出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-021-03292-3
关键词
Alpha-synuclein; Iron; Endoplasmic reticulum stress; Parkinson’ s disease
资金
- National Natural Science Foundation of China [31871049, 31771124, 31900745]
- Excellent Innovative Team of Shandong Province
- Taishan Scholars Construction Project
The research indicates that extracellular alpha-synuclein can regulate cellular iron metabolism, potentially mediated by ER stress. This provides novel evidence to elucidate the relationships between transmitted alpha-synuclein and iron metabolism disturbance in PD.
Alpha-synuclein plays a vital role in the pathology of Parkinson's disease (PD). Spreading of alpha-synuclein in neighboring cells was believed to contribute to progression in PD. How alpha-synuclein transmission affects adjacent cells is not full elucidated. Here, we used recombinant alpha-synuclein to mimic intercellular transmitted alpha-synuclein in MES23.5 dopaminergic cells, to investigate whether and how it could modulate iron metabolism. The results showed that alpha-synuclein treatment up-regulated divalent metal transporter 1 (DMT1) and down-regulated iron transporter (FPN), also up-regulated iron regulatory protein 1 (IRP1) protein levels and hepcidin mRNA levels. Endocytosis inhibitor dynasore pretreatment completely abolished and even reversed the upregulation of DMT1 and IRP1 induced by alpha-synuclein, however, FPN down-regulation was partially blocked by dynasore. Autophagy-inducing agent rapamycin reversed DMT1 up-regulation and FPN down-regulation, and fully blocked the upregulation of IRP1. Elevated hepcidin levels induced by alpha-synuclein was fully blocked by dynasore pretreatment, however, even higher with rapamycin pretreatment. Alpha-synuclein treatment triggered endoplasmic reticulum (ER) stress. ER stress inducer thapsigargin induced similar responses elicited by alpha-synuclein. ER stress inhibitor salubrinal blocked the up-regulation of IRP1 and hepcidin, as well as DMT1 up-regulation and FPN down-regulation, also dramatically abolished cAMP-response elements binding protein phosphorylation induced by alpha-synuclein. Taken together, these finding indicated that extracellular alpha-synuclein could regulate cellular iron metabolism, probably mediated by ER stress. It provides novel evidence to elucidate the relationships between transmitted alpha-synuclein and iron metabolism disturbance in PD.
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