title: 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 (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) 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-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) 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 PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). 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 PrP(C) 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 PrP(C) that is likely to impact the therapeutic management of CH and sCJD.
authors.forename: Ajai K
authors.initials: AK
authors.lastname: Tripathi
authors.forename: Neena
authors.initials: N
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D045744:Cell Line, Tumor; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000473:pathology*; D004705:Endocytosis / Q000187:drug effects; D005293:Ferritins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006427:Hemin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D000072002:Prion Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D006454:Hemoglobins; D000072002:Prion Proteins; D049452:Green Fluorescent Proteins; D006427:Hemin; D005293:Ferritins
keywords: hemin; neuronal hemoglobin; prion protein; sCJD; α-Globin
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