Two papers reviewed in this issue of Neurology Today address the role of the prion protein (PrPc) in health and disease. In one study — by Adriano Aguzzi, MD, PhD, and colleagues — mice in whom the gene encoding PrPc was ablated developed a demyelinating polyneuropathy. Surprisingly this phenotype appeared to result specifically from loss of expression of the normal PrPc in neurons rather than Schwann cells.
These studies suggest that one of the roles of normal neuronal PrPc is to facilitate maintenance of peripheral myelin. This result would not have been predicted from knowledge of the clinical phenotypes of diseases that occur in association with accumulation of abnormal forms of the prion protein (PrPres) in humans or animals, as neither acquired or genetic forms of prion disease are typically associated with significant peripheral nervous system pathology.
The second paper reviewed in this issue by Bruce Chesebro, PhD, and colleagues, describes a novel phenotype occurring in mice expressing a truncated form of PrPc that lacks the glycosylphosphatidylinositol moiety that serves to anchor the protein to cell membranes.
Transgenic mice expressing high levels of anchorless PrPc are phenotypically normal. However, when these mice are injected with scrapie prions they develop a novel form of prion disease characterized by amyloid angiopathy associated with vascular and perivascular deposition of PrPres. These animals lacked the neuronal spongiform degeneration characteristic of many forms of prion disease. As a result, the pathology more closely resembled that of cerebral amyloid angiopathy as seen in humans, rather than that of Creutzfeldt-Jakob disease or related diseases.
The surprise here is that the disease phenotype can differ so dramatically in its manifestations depending on whether the prion protein is anchored to membranes or soluble.
Taken together these two papers remind us that we still have much to learn regarding how PrPc functions normally in the nervous system and how accumulation of different forms of abnormal PrP induce disease. •