Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders.
Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders.
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prion蛋白促进视网膜铁吸收，并在β地点裂解：对视网膜铁稳态的影响。
DOI：
10.1038/s41598-017-08821-1
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发表时间：
2017-08-29
影响因子：
4.6
通讯作者：
Singh N
中科院分区：
文献类型：
--
作者：
Asthana A;Baksi S;Ashok A;Karmakar S;Mammadova N;Kokemuller R;Greenlee MH;Kong Q;Singh N
PrP-scrapie(PrPSc)是PrP蛋白(PrPC)的一种错误折叠形式，积聚在神经视网膜中。然而，PrPSc和细胞毒性之间缺乏时间和空间相关性，这表明宿主因素起到了作用。我们报告视网膜铁代谢紊乱是其中的一个因素。PrPC表达在视网膜色素上皮(RPE)细胞的基侧膜上，在那里它介导神经视网膜对铁的摄取。因此，PrP基因敲除小鼠的神经视网膜缺铁。在RPE19细胞中，PrPC的沉默降低了铁蛋白，而过表达则上调了铁蛋白和二价金属转运体-1(DMT-1)，表明PrPC通过DMT-1介导铁摄取。RPE19细胞的极化导致铁蛋白上调~10倍，PrPC的β-裂解，后者可能通过裂解铁还原酶域而阻止铁的进一步摄取。在小鼠视网膜裂解物中也观察到类似的PrPC的β裂解。瘙痒病感染会导致PrPSc积聚和小胶质细胞激活，令人惊讶的是，尽管铁蛋白水平上升，转铁蛋白仍上调。值得注意的是，洗涤剂不溶于铁蛋白在RPE细胞中积聚，并与小胶质细胞激活有关，而不是PrPSc的积聚，这表明PrPSc对铁的摄取受损与炎症共同导致视网膜铁代谢紊乱，这是一种潜在的毒性宿主反应，有助于PrPSc疾病相关的病理。
Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrPSc), a misfolded isoform of prion protein (PrPC) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrPSc and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrPC is expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient. In RPE19 cells, silencing of PrPC decreases ferritin while over-expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrPC-mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and β-cleavage of PrPC, the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar β-cleavage of PrPC is observed in mouse retinal lysates. Scrapie infection causes PrPSc accumulation and microglial activation, and surprisingly, upregulation of transferrin despite increased levels of ferritin. Notably, detergent-insoluble ferritin accumulates in RPE cells and correlates temporally with microglial activation, not PrPSc accumulation, suggesting that impaired uptake of iron by PrPSc combined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology.
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影响因子：
9.8
作者：
Alibhai J;Blanco RA;Barria MA;Piccardo P;Caughey B;Perry VH;Freeman TC;Manson JC
通讯作者：
Manson JC
影响因子：
7.4
作者：
Baksi S;Tripathi AK;Singh N
通讯作者：
Singh N
影响因子：
6
作者：
Greenlee, M. Heather West;Lind, Melissa;Greenlee, Justin
通讯作者：
Greenlee, Justin
DOI：
10.1016/j.jtemb.2016.03.010
发表时间：
2016-01-01
影响因子：
3.5
作者：
Dusek, Petr;Schneider, Susanne A.;Aaseth, Jan
通讯作者：
Aaseth, Jan
影响因子：
8
作者：
Haigh, C. L.;McGlade, A. R.;Collins, S. J.
通讯作者：
Collins, S. J.