Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease.
Alpha-synuclein modulates retinal iron homeostasis by facilitating the uptake of transferrin-bound iron: Implications for visual manifestations of Parkinson's disease.
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DOI：
10.1016/j.freeradbiomed.2016.06.025
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发表时间：
2016-08
影响因子：
7.4
通讯作者：
Singh N
中科院分区：
文献类型：
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作者：
Baksi S;Tripathi AK;Singh N
黑质神经元中α-突触核蛋白(α-SYN)的聚集是帕金森病(PD)的诊断依据，帕金森病是一种视觉症状突出的神经运动障碍。在这里，我们证明了参与帕金森病发病机制的主要蛋白α-SYN在神经视网膜中广泛表达，并促进形成外部血-视网膜屏障的视网膜色素上皮细胞摄取转铁蛋白结合铁(Tf-Fe)。在基因敲除的小鼠中，α-SYN的缺失(α-SYN−/−)导致了神经视网膜中铁蛋白的下调，这表明细胞铁储存的耗尽。在α-SYN−/−小鼠的脾、股骨和脑组织中也观察到类似的缺铁表型，这些器官主要利用Tf-Fe来满足其代谢需要。肝脏和肾脏这两个吸收大量非转铁蛋白结合铁(NTBI)的器官表现出很小的变化。对人RPE47细胞系的潜在机制的评估表明，α-SYN通过调节转铁蛋白(Tf)/转铁蛋白受体(TfR)复合体的内吞和循环，在Tf-Fe的摄取中发挥显著作用。RNAi下调视网膜色素上皮细胞中α-SYN的表达，导致常见的循环内小体(CRE)中Tf/TfR复合体的积聚，表明细胞对质膜的再循环受到干扰。外源性α-SYN在视网膜色素上皮细胞中过表达，铁蛋白和转铁蛋白受体表达上调。有趣的是，暴露于外源铁增加了α-SYN与转铁蛋白受体的膜结合和共定位，支持了它在转铁蛋白/转铁蛋白受体复合体的铁摄取中的作用。结合我们的观察表明α-SYN和TfR在活体视网膜色素上皮细胞上的基侧表达，本研究揭示了α-SYN在神经视网膜摄取Tf-Fe方面的新功能。可能是由于α-SYN功能受损或改变所致的视网膜铁代谢紊乱导致了与PD相关的视觉症状。
Aggregation of α-synuclein (α-syn) in neurons of the substantia nigra is diagnostic of Parkinson’s disease (PD), a neuro-motor disorder with prominent visual symptoms. Here, we demonstrate that α-syn, the principal protein involved in the pathogenesis of PD, is expressed widely in the neuroretina, and facilitates the uptake of transferrin-bound iron (Tf-Fe) by retinal pigment epithelial (RPE) cells that form the outer blood-retinal barrier. Absence of α-syn in knock-out mice (α-syn−/−) resulted in down-regulation of ferritin in the neuroretina, indicating depletion of cellular iron stores. A similar phenotype of iron deficiency was observed in the spleen, femur, and brain tissue of α-syn−/− mice, organs that utilize mainly Tf-Fe for their metabolic needs. The liver and kidney, organs that take up significant amounts of non-Tf-bound iron (NTBI), showed minimal change. Evaluation of the underlying mechanism in the human RPE47 cell line suggested a prominent role of α-syn in the uptake of Tf-Fe by modulating the endocytosis and recycling of transferrin (Tf)/transferrin-receptor (TfR) complex. Down-regulation of α-syn in RPE cells by RNAi resulted in the accumulation of Tf/TfR complex in common recycling endosomes (CREs), indicating disruption of recycling to the plasma membrane. Over-expression of exogenous α-syn in RPE cells, on the other hand, up-regulated ferritin and TfR expression. Interestingly, exposure to exogenous iron increased membrane association and co-localization of α-syn with TfR, supporting its role in iron uptake by the Tf/TfR complex. Together with our observations indicating basolateral expression of α-syn and TfR on RPE cells in vivo, this study reveals a novel function of α-syn in the uptake of Tf-Fe by the neuroretina. It is likely that retinal iron dyshomeostasis due to impaired or altered function of α-syn contributes to the visual symptoms associated with PD.