Aged PrP null mice show defective processing of neuregulins in the peripheral nervous system

A prion, a protease-resistant conformer of the cellular prion protein (PrPC), is the causative agent of transmissible spongiform encephalopathies or prion diseases. While this property is well established for the aberrantly folded protein, the physiological function of PrPC remains elusive. Among different putative functions, the non-pathogenic protein isoform PrPC is involved in several cellular processes. Here, we show that PrPC regulates the cleavage of neuregulin-1 proteins (NRG1). Neuregulins provide key axonal signals that regulate several processes, including glial cells proliferation, survival and myelination. Interestingly, mice devoid of PrPC (Prnp0/0) were recently shown to have a late-onset demyelinating disease in the peripheral nervous system (PNS) but not in the central nervous system (CNS). We found that NRG1 processing is developmentally regulated in the PNS and, by comparing wildtype and Prnp0/0 mice, that PrPC influences NRG1 processing in old, but not in young, animals. In addition, we found that also the processing of neuregulin-3, another neuregulin family member, is altered in the PNS of Prnp0/0 mice. These differences in neuregulin proteins processing are not paralleled in the CNS, thus suggesting a different cellular function for PrPC between the CNS and the PNS.