Bremer, J. et al. Axonal prion protein is required for peripheral myelin maintenance. Nature Neurosci. 13, 310-318

Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Nature Neuroscience (Impact Factor: 16.1). 03/2010; 13(3):310-8. DOI: 10.1038/nn.2483
Source: PubMed


The integrity of peripheral nerves relies on communication between axons and Schwann cells. The axonal signals that ensure myelin maintenance are distinct from those that direct myelination and are largely unknown. Here we show that ablation of the prion protein PrP(C) triggers a chronic demyelinating polyneuropathy (CDP) in four independently targeted mouse strains. Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse strains, did not modulate the CDP. CDP was triggered by depletion of PrP(C) specifically in neurons, but not in Schwann cells, and was suppressed by PrP(C) expression restricted to neurons but not to Schwann cells. CDP was prevented by PrP(C) variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrP(C) lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrP(C) are essential for myelin maintenance.

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    • "The cellular form of the prion protein (PrP C ), encoded by the Prnp gene, is displayed on the cell surface by a glycophosphatidylinositol (GPI) anchor and serves a precursor role, undergoing a change from a mainly alpha-helical structure to the beta-rich conformation of PrP Sc during disease. Its function is debated such that it could be involved in neuroprotection (Kuwahara et al, 1999; Weise et al, 2004; Watt et al, 2005; Rangel et al, 2007), copper homeostasis (Pauly & Harris, 1998; Herms et al, 1999; Millhauser, 2004, 2007), signal transduction (Mouillet-Richard et al, 2000; Spielhaupter & Schatzl, 2001; Chiarini et al, 2002) or peripheral myelin maintenance (Nishida et al, 1999; Bremer et al, 2010). In structural terms, PrP C is composed of a flexible N-terminal region (including a charged patch), two hexarepeats, five tandem repeats of eight amino acids forming an octarepeat region (OR), a hydrophobic linker region sometimes referred to as the 'HD' (hydrophobic domain) and a C-terminal globular domain (Fig 1A). "
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    ABSTRACT: The cellular prion protein (PrP(C)) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrP(S) (c) in Creutzfeldt-Jakob disease. PrP(C) β-endoproteolysis to the C2 fragment allows PrP(S) (c) formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, 'S1' and 'S3', locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrP(S) (c) and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrP(S) (c) and infectivity can either uncouple or engage to drive the onset of clinical disease. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Feb 2015 · EMBO Molecular Medicine
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    • "The most studied phenotype of Prnp −/− mice is myelin degeneration . This phenotype is seen in both type 1 and type 2 Prnp −/− mice (Nishida et al., 1999; Baumann et al., 2007; Bremer et al., 2010). The myelin degeneration phenotype is caused by a deficiency of PrP C , suggesting that myelin maintenance may be a representative physiological function of PrP C . "
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    ABSTRACT: Elucidation of prion protein (PrP) functions is crucial to fully understand prion diseases. A major approach to studying PrP functions is the use of PrP gene-knockout (Prnp-/-) mice. So far, six types of Prnp-/- mice have been generated, demonstrating the promiscuous functions of PrP. Recently, other PrP family members, such as Doppel and Shadoo, have been found. However, information obtained from comparative studies of structural and functional analyses of these PrP family proteins do not fully reveal PrP functions. Recently, varieties of Prnp-/- cell lines established from Prnp-/- mice have contributed to the analysis of PrP functions. In this mini-review, we focus on Prnp-/- cell lines and summarize currently available Prnp-/- cell lines and their characterizations. In addition, we introduce the recent advances in the methodology of cell line generation with knockout or knockdown of the PrP gene. We also discuss how these cell lines have provided valuable insights into PrP functions and show future perspectives.
    Full-text · Article · Jan 2015 · Frontiers in Cell and Developmental Biology
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    • "Electrophysiology NCV were measured in 4-month-old anesthetized mice as described (Bremer et al., 2010). Briefly, upon stimulation of the tibial nerve at the ankle (''distal'') and of the sciatic nerve at the sciatic notch (''proximal''), compound muscle action potentials (CMAPs), measuring motor NCV, were recorded from the foot muscle. "
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    ABSTRACT: Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRγ, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXRγ-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
    Full-text · Article · Oct 2014 · Cell Reports
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