Credit: PHOTOALTO

Mutated forms of PrPC, the endogenous prion protein, are linked to transmissible spongiform encephalopathies, but the normal function of PrPC has yet to be identified. Bremer et al. now show that neuronal expression of PrPC is necessary for the maintenance of the myelin sheaths around peripheral nerves.

Mice lacking PrPC are resistant to prion infections but sometimes show peripheral neuropathy. The authors therefore investigated the possible role of PrPC in peripheral nerves. PrPC-deficient mice (prnp−/− mice) showed demyelinating polyneuropathy in all peripheral nerves by 60 weeks of age, including thinned myelin sheaths and 'onion bulbs', which result from repeated demyelination and remyelination. Signs of neuropathy were evident in 10- and 30-week-old animals, indicating that the pathogenic process starts immediately after the completion of peripheral myelination. There was no myelin degeneration in central nerves.

Surprisingly, the authors showed that re-expressing PrPC specifically in neurons of prnp−/− mice prevented the polyneuropathy, whereas expressing PrPC in myelinating Schwann cells did not. Conversely, polyneuropathy was induced by PrPC depletion in neurons but not by PrPC depletion in Schwann cells. Thus, neuron-specific expression of PrPC is required for maintaining peripheral myelin.

As PrPC can undergo proteolytic cleavage, the authors next investigated whether this process is important for the role of PrPC in maintaining peripheral myelin. Transgenic mice expressing PrPC but lacking its membrane anchor showed no proteolytic PrPC cleavage and had polyneuropathy similar to that of prnp−/− mice. Furthermore, sciatic nerves from transgenic mice expressing a PrPC variant lacking part of the amino-proximal domain were deficient in certain PrPC cleavage fragments and also showed demyelinating neuropathy, as did mice lacking the hydrophobic core of this domain. This suggests that PrPC must be capable of undergoing proteolysis to preserve the integrity of peripheral myelin.

The finding that neuronal expression of PrPC is required for maintaining the myelin sheaths of peripheral nerves suggests that PrPC might mediate axon–Schwann cell communication; it is possible that PrPC cleavage products interact with receptors on Schwann cells. Reducing the levels of PrPC has been suggested as a potential strategy to prevent neurodegeneration in prion diseases, but this study shows that such an approach might have deleterious side effects.