Histology and immunohistochemical analysis of frontal cortex samples of the brain of a patient who died of noncerebral causes (upper row) and a patient

suffering from Creutzfeldt-Jakob … Despite the amount of information that has been accrued, all of these studies suffer from the fundamental problem that it is not clear whether the phenomenon observed in conjunction with exposure of cells to this small amyloidogenic peptide Inhibitors,research,lifescience,medical bear much relevance to what is happening in vivo during the course of prion replication – a process that may arguably be very different. Moreover, some of the published data have recently been challenged.49 In order to ask the simple question of whether cerebral accumulation of PrPSc in the extracellular space suffices to damage nerve cells, we have undertaken fetal neuroectodermal transplantation experiments.50 Histological analysis of PrP-deficient mice that had been grafted with brain cells derived from transgenic mice overexpressing PrPC

and subsequently Inhibitors,research,lifescience,medical infected with prions indicated that pathology is confined to the regions of the brain that express PrPC. In the surrounding PrPCdeficient brain, no pathological changes could be detected even though substantial accumulations of pathological PrPSc occurred.50 While the Inhibitors,research,lifescience,medical PD98059 in vivo interpretation of this experiment is liable to certain caveats (most notably the possibility that a threshold concentration of PrPSc is needed for induction of neurodegeneration and is not attained outside the grafted tissue), it is difficult to avoid the

conclusion Inhibitors,research,lifescience,medical that the neuronal cytotoxicity of PrPSc is dependent on the expression of cellular PrPC by target cells. Why should that be? Perhaps PrPC acts as a receptor for PrPSc. However, it has never been possible to demonstrate an affinity between these two moieties. Alternatively, the conversion process of PrPC into PrPSc itself, rather than exposure to the disease-associated prion protein, may constitute the primary deleterious event. The latter possibility has been thoroughly Inhibitors,research,lifescience,medical investigated in a series of elegant papers 4-Aminobutyrate aminotransferase by Lingappa and coworkers. These authors have identified an atypical form of PrPC that undergoes a peculiar biogenesis (Figure 4).51-54 Most cellular PrPC is secreted into the lumen of the endoplasmic reticulum (ER) by virtue of its secretory signal peptide, where it is routed to the cell surface as a glycophosphoinositol-linked membrane-associated protein. However, a small proportion of PrPC remains stuck in the ER membrane as a transmembrane protein. Depending on their orientation, Lingappa and coworkers have termed these proteins CtmPrP and NtmPrP (for carboxy- and amino-terminal transmembrane, respectively).55,56 By quantifying the production of CtmPrP in pathological conditions, they found that it correlates very well with the neurodegenerative changes – in fact much better than the accumulation of PrPSc itself.