Prion Protein Receptor Research Articles

Receptor for prion protein identified

Prion proteins are infamous for going rogue. In the brain, misfolded versions of the proteins can convert normally folded prions into forms that cause neurodegenerative diseases such as mad cow disease and fatal familial insomnia. But researchers know little about the everyday function of prions. A team of scientists now report that the proteins bind to a specific cell receptor to help maintain the electrical insulation on nerve cells outside of the brain (Nature 2016, DOI: 10.1038/nature19312). In 2010, Adriano Aguzzi of the University of Zurich and colleagues reported that mice engineered to lack the prion protein gene lost this lipid-and-protein coating, which is called myelin. Now, through a series of experiments, Aguzzi’s team demonstrates that a 28-amino-acid sequence on one end of the prion protein binds to and activates a receptor called Gpr126 on Schwann cells, which are responsible for maintaining myelin sheaths. Once activated, these receptors trigger cellular

Investigating the Interaction Between Characterized Amyloid-Beta Oligomers and the Prion Protein Receptor in Live Cells

The devastating symptoms of Alzheimer's disease (AD) have been attributed to the aberrant aggregation of amyloid-β (Aβ) peptides generated from proteolytic cleavage of the transmembrane receptor, amyloid precursor protein (APP). Oligomers of the peptides amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) have been implicated in cytotoxicity and impaired cognitive function associated with AD1,2. Due to their heterogeneous nature, characterizing these oligomers on a molecular level and understanding the mechanism by which they induce cellular damage and death has proven to be difficult for conventional biochemical techniques. In this work, we use two color total internal reflection fluorescence microscopy first to characterize various preparations of Aβ oligomers on a molecular-level and then to explore the interactions of these well-characterized mixtures with live cells. Among the cellular systems examined include those expressing the prion protein receptor (PrPc) which, in recent studies, has been suggested to have a key role in mediating the toxic effects of Aβ oligomers3. From these studies we have not only been able to gain insight into the relationship between Aβ oligomers and PrPc on live cells but also have developed a methodology for examination of receptor-mediated Aβ neurotoxicity.1. Chiti, F. & Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry 75, 333-366 (2006).2. Cleary, J.P. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nature Neuroscience 8, 79-84 (2005).3. Lauren, J., Gimbel, D.A., Nygaard, H.B., Gilbert, J.W. & Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128-1132 (2009).

Intestinal entry of prions.

Variant Creutzfeldt-Jakob disease is thought to be caused by infected prion protein via ingestion of contaminated beef. After ingestion of infected prion proteins, uptake by small intestine may be by either M-cell dependent or M-cell independent routes. A receptor for prion protein, laminin receptor precursor is expressed on the brush border of small intestinal epithelium in 40 % of subjects. The cellular prion protein expressed on the enteric nervous system might serve as the target for conversion to infectious prion protein and a route for spread to the central nervous system.

Complementary hydropathy identifies a cellular prion protein receptor.

Prions, the etiological agents for infectious degenerative encephalopathies, act by entering the cell and inducing conformational changes in PrPC (a normal cell membrane sialoglycoprotein), which result in cell death. A specific cell-surface receptor to mediate PrPC and prion endocytosis has been predicted. Complementary hydropathy let us generate a hypothetical peptide mimicking the receptor binding site. Antibodies raised against this peptide stain the surface of mouse neurons and recognize a 66-kDa membrane protein that binds PrPC both in vitro and in vivo. Furthermore, both the complementary prion peptide and antiserum against it inhibit the toxicity of a prion-derived peptide toward neuronal cells in culture. Such reagents might therefore have therapeutic applications.