It is another fine work published in PLOS.

However, I think that some parts deserve further consideration. For instance: “The signal sequence of PrP has evolved to maintain a slight but measurable inefficiency in interaction with the translocon [42], [48].” Seems to me, to be a form of speculation while, “ It is therefore tempting to speculate that PrP might have acquired the ability to adopt cytosolic or transmembrane topologies with opposite effects on neuronal survival for a functional purpose, perhaps to fine-tune signaling cascades that control cell fate in the developing brain [2],” is not an speculation since the data clearly indicate two opposite effects according to the cell type studied. See for instance: “However, several observations undermine the idea that cytosolic PrP is invariably neurotoxic. In non-pathogenic conditions, PrP was found in the cytoplasm of some neuronal populations in the hippocampus, neocortex and thalamus, with no signs of neurodegeneration [20], [21], [22]. Then too, analysis of cytosolic PrP activity in different cells produced conflicting results: whereas some studies confirmed the toxicity [11], [16], [23], [24], [25], others did not [15], [26], [27], and some brought to light a protective effect against Bax-mediated cell death [28], [29]. These observations raised the possibility that cells of different neural origin could differ in their propensity to synthesize PrP in the cytosol, and that this isoform could have cell type-specific biological activities.”
It seems that despite clear perception by some scientific researchers that in some cases sequence alone does not allows for determination of function …For instance, those scientists that considers that geneticists should be more humble in their interpretation of data. It seems that, a major critical analyses demonstrating how the pathways followed by science in the last 40 years or so, led to a dogmatic point of view still prevailing today despite all scientific data indicating its limits.
This work clearly indicates that in presence of one microenvironment a protein may have one function while in another microenvironment (another cell with the same genome) it may have an opposite function.