title: Aged PrP null mice show defective processing of neuregulins in the peripheral nervous system.
abstract: A prion, a protease-resistant conformer of the cellular prion protein (PrP(C)), 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 PrP(C) remains elusive. Among different putative functions, the non-pathogenic protein isoform PrP(C) is involved in several cellular processes. Here, we show that PrP(C) 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 PrP(C) (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 PrP(C) 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 PrP(C) between the CNS and the PNS.
authors.affiliation: Laboratory of Prion Biology, Neurobiology Sector, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, I-34136 Trieste, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Benvegnù
authors.forename: Lisa
authors.initials: L
authors.lastname: Gasperini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020880:Neuregulins / Q000378:metabolism*; D017933:Peripheral Nervous System / Q000503:physiopathology*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020880:Neuregulins; D011328:Prions; D051076:Proto-Oncogene Proteins c-fyn; D048049:Extracellular Signal-Regulated MAP Kinases