Week X and Final Goals

I apologize for the lateness of this final summery; tying up the scope of my research has been tricky and required a long period of meditation.

I have previously explained the general mechanism for the proliferation of the scrapie isoform of the normal PrPC protein expressed on the surface of a number of cells, including T cells, B cells, follicular dendritic cells, dendritic cells, microglia, astrocytes, oligodendrocytes, and critically on CNS neurons. Though the function of PrPC on neurons a large number of possibilities including ion uptake and signal transduction, a loss of function following an effective degree of PrPSc-induced conversion results in the overproduction of reactive oxygen species and eventual apoptotic state of the neuron. Neuronal death within the brain and CNS triggers a local inflammatory response principally carried out by microglia, which are in intercellular contact with astrocytes and oligodendrocytes. Prion infection of these cells can also led to multiple losses of function and misregulation leading to an increase of pro-inflammatory cytokines, ion efflux, and increased non-specific phagocytic activity, upregualted productions of ROS and RNS, and possibly demyelination, all compounding on the increasingly apoptotic state of the neurons.

In my model I have illustrated a method for prion neuroinvasion following peripheral infection of an ingested portion on the scrapie protein. The prion protein is most likely taken up from the intestinal lumen in  the form of large aggretates, potentially secured within lipid rafts. M cells interspersed with epithelial cells can take in these aggregates and pass them on to Peyer’s Patches or be taken up/cross-infect present dendritic cells. Monocytes may also be implicated in this process. The aggregates may be transferred to germinal centers, and replicate on FDCs. When enough PrPSc has been replicated by the PrPC-expressing FDC and it can then leave germinal centers via B cell interactions with T cells, which recirculate into the blood which may be retargeted to areas of inflammation like the brain, accelerating the clinical phase of the disease later. PrPSc may first cross the blood-brain barrier via passive exchange of bone-marrow derived monocytes and local CNS dendritic cells and microglia in the perivascular space or a previous infection. PrPSc does not likely directly enter the spleen as it does lymph nodes and Peyer’s patches, but after its circulation in to the blood stream. Once in the spleen, it can replicate in a similar manner.

The induced conformational change of PrPC to the scrapie version is highly specific, and because it is derived from a normal cellular component, it does not excite a normal immune response, which places a very serious limitation on treatment of prion disease. Treatment proposals range from alleviation of brain inflammation by triggering upreguation of anti-inflammatory signals to monoclonal antibodies to induce a prion-specific immune response that does not also target the normal isoform. I will consider placing some of these treatments in my model, but may desire harder clinical evidence showing successes. Prion disease is not a widespread threat to the human populations and there have been highly localized outbreaks in the past and limited cases now. But, because prion disease effects the human neural system in a similar manner to Alzheimer’s, my research could contribute to a greater understanding of neurodegeneration and areas most effected by agents of neurodegeneration.