Affiliations: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
Correspondence:
[*]
Correspondence to: Neena Singh, Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Tel.: +1 2163682617; Fax: +1 2163680494; E-mail: [email protected].
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.
