Laboratory of Prion Biology, Neurobiology Sector, Scuola Internazionale Superiore di Studi Avanzati (SISSA), via Bonomea 265, I-34136 Trieste, Italy.
Mol Cell Neurosci. 2011 May;47(1):28-35. doi: 10.1016/j.mcn.2011.02.005. Epub 2011 Feb 17.
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.
朊病毒是细胞朊蛋白（PrP(C)）的一种抗蛋白酶构象，是传染性海绵状脑病或朊病毒病的致病因子。虽然这种异常折叠的蛋白质的特性已经得到很好的证实，但 PrP(C) 的生理功能仍然难以捉摸。在不同的假定功能中，非致病性蛋白异构体 PrP(C) 参与了几种细胞过程。在这里，我们表明 PrP(C) 调节神经调节蛋白-1 蛋白（NRG1）的切割。神经调节蛋白提供关键的轴突信号，调节包括神经胶质细胞增殖、存活和髓鞘形成在内的多个过程。有趣的是，最近研究表明，缺乏 PrP(C)（Prnp⁰/⁰）的小鼠在周围神经系统（PNS）而不是中枢神经系统（CNS）中会出现迟发性脱髓鞘疾病。我们发现，NRG1 的加工在 PNS 中受到发育调控，并且通过比较野生型和 Prnp⁰/⁰ 小鼠，PrP(C) 影响老年动物而不是年轻动物的 NRG1 加工。此外，我们发现，另一种神经调节蛋白家族成员神经调节蛋白-3 的加工在 Prnp⁰/⁰ 小鼠的 PNS 中也发生改变。这些神经调节蛋白蛋白加工的差异在 CNS 中并不平行，因此表明 PrP(C) 在 CNS 和 PNS 之间具有不同的细胞功能。
