Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease.
Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease.
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DOI：
10.3233/jad-151039
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Singh N
中科院分区：
文献类型：
--
作者：
Tripathi AK;Singh N
已知氯化血红素可诱导神经细胞质膜上的PrPC内吞，潜在地限制了引起PrP-scrapie(PrPSc)亚型的疾病的传播。因此，氯化血红素是治疗散发性克雅氏病(SCJD)的一种有吸引力的疾病修改选择，sCJD是一种没有有效治疗方法的人类普恩疾病。氯化血红素-PrPC的相互作用在脑出血(CH)中也很有意义，这种情况下潜在的有毒氯化血红素分子与神经元PrPC接触。有趣的是，PrPC在CH周围的半峰神经元中上调，并以剂量依赖的方式提供神经保护。然而，潜在的机制尚不清楚。在这里，我们报告了氯化血红素与不同细胞系上的PrPC结合，导致其以细胞类型特异性的方式聚集或降解。令人惊讶的是，氯化血红素-PrPC相互作用上调了造血细胞中Hb的合成，这一反应被删除PrPC的氯化血红素结合八肽重复区域逆转。在大脑器官型培养中也注意到类似的反应，暴露于氯化血红素在野生型(PrP+/+)中诱导的α-珠蛋白明显多于PrP-敲除(PrP-−/−)样本。此外，PrP−/−小鼠的红细胞和脑组织显示的α-珠蛋白显著低于PrP+/+对照组，这表明在生理条件下PrPC对Hb的合成也有积极的影响。令人惊讶的是，SCJD脑组织中α-珠蛋白的水平明显高于对照组，这表明幸存的神经元或疾病大脑中的错误调节导致了Hb合成的代偿性上调。这些观察揭示了PrPC的独特功能，可能会影响CH和sCJD的治疗。
Hemin is known to induce endocytosis of prion-protein (PrPC) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrPSc) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrPC interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrPC. Interestingly, PrPC is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrPC on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrPC interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrPC. A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP+/+) relative to PrP-knock-out (PrP−/−) samples. Furthermore, red blood cells and brain tissue from PrP−/− mice show significantly less α-globin relative to PrP+/+ controls, indicating a positive effect of PrPC on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrPC that is likely to impact the therapeutic management of CH and sCJD.
影响因子：
3.7
作者：
Singh A;Beveridge AJ;Singh N
通讯作者：
Singh N