Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease

Abstract

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.

Transport of Non-Transferrin Bound Iron to the Brain: Implications for Alzheimer’s Disease

“…SDS-PAGE and western blotting [34], native gel electrophoresis [35], Perls’ staining [36], immunostaining [37], and quantitative RT-PCR were performed essentially as described [38, 39]. …”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…However, the binding interaction also significantly upregulates hemoglobin synthesis in hematopoietic cells, where brain organotype cultures exposed to hemin showed increased α-globin in PrP WT compared to PrP knockout samples. Additionally, RBCs from PrP knockout mice had markedly lower α-globin levels compared to PrP WT controls [ 614 ]. Since heme regulates gene expression transcriptionally and post-transcriptionally [ 615 , 616 ], heme can initiate changes in key factors that control extensive processes from cell cycle and Ras signaling to chromatin structure, splicing, and protein folding [ 617 , 618 ].…”

Interaction between Hemin and Prion Peptides: Binding, Oxidative Reactivity and Aggregation

“…There is also evidence that hemin can interact with prion proteins [ 34 , 35 , 36 ], and the relevance of this interaction has been recently confirmed [ 37 ]. Moreover, biomimetic porphyrins and phthalocyanines containing iron (III) inhibit the conversion of cellular prion protein into the abnormal isoform in vitro, acting as potential protectors in transmissible spongiform encephalopathies [ 38 ].…”

“…Moreover, biomimetic porphyrins and phthalocyanines containing iron (III) inhibit the conversion of cellular prion protein into the abnormal isoform in vitro, acting as potential protectors in transmissible spongiform encephalopathies [ 38 ]. Based on these observations, the possibility that hemin is a natural binding agent for PrP C and acts as a neuro-protector in pathological conditions such as sCJD and cerebral hemorrhage, characterized by a significant increase concentration of free hemin, has been postulated [ 37 ].…”