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Axonal prion protein is required for peripheral myelin maintenance

Nature Neuroscience volume 13, pages 310–318 (2010)Cite this article

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Abstract

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 PrPC 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 PrPC specifically in neurons, but not in Schwann cells, and was suppressed by PrPC expression restricted to neurons but not to Schwann cells. CDP was prevented by PrPC variants that undergo proteolytic amino-proximal cleavage, but not by variants that are nonpermissive for cleavage, including secreted PrPC lacking its glycolipid membrane anchor. These results indicate that neuronal expression and regulated proteolysis of PrPC are essential for myelin maintenance.

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Figure 1: Peripheral polyneuropathy in Prnpo/o mice.
Figure 2: Ultrastructural alterations in Prnpo/o sciatic nerves.
Figure 3: Electrophysiology and behavior of Prnpo/o mice.
Figure 4: Expression of PrPC by neurons is essential for myelin sheath maintenance.
Figure 5: Neuron-specific but not Schwann cell–specific depletion of PrPC induces polyneuropathy.
Figure 6: PrPC expression and proteolytic processing in sciatic nerves of wild-type and tgGPI−PrP mice.
Figure 7: Role of N-terminal domains and lymphocytes in the pathogenesis of Prnpo/o polyneuropathy.

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Acknowledgements

We thank M. Delic, R. Moos, D. Goriounov, C. Tostado, H. Mader, K. Nairz, M. Bieri, N. Wey and D. Meijer for methodological advice and technical help. G. Mallucci provided tgNFH-Cre and tgPrnploxP mice, D. Meijer provided tgDhh-Cre mice, J.C. Manson provided PrnpEdbg/Edbg mice, J. Collinge provided Prnpo/o FVB mice, S. Lindquist and W. Jackson provided PrnpGFP/GFP mice and P. Saftig and A. Rittger provided nerves from BACE1−/− mice. We thank W.B. Macklin for the PLP plasmid; T. Rülicke for pronuclear injections and H. Welzl, I. Drescher and S. Wirth for help with behavioral tests. J.A. Girault and M.T. Dours-Zimmermann donated anti-paranodine/Caspr and anti-versican antibodies, respectively. We thank B. Seifert for statistical consulting. A.A. received an ERC Advanced Investigator Grant and grants from the European Union (PRIORITY and LUPAS), the Novartis Foundation and the Swiss National Foundation. J.B. received a Career Development award from the University of Zürich. C.W. and K.V.T. were supported by the Departmental Research Fund.

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Authors and Affiliations

  1. Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland

    Juliane Bremer, Frank Baumann, Cinzia Tiberi, Heike Fischer, Petra Schwarz & Adriano Aguzzi

  2. Department of Neurology, University of Würzburg, Würzburg, Germany

    Carsten Wessig & Klaus V Toyka

  3. Division of Biology, California Institute of Technology, Pasadena, California, USA

    Andrew D Steele

  4. Department of Neurogenetics, Max-Planck Institute of Experimental Medicine, Göttingen, Germany

    Klaus-Armin Nave

  5. Institute of Neuropathology, Medical Faculty, Rheinisch-Westfälische Technische Hochschule (RWTH,

    Joachim Weis

  6. ) University Aachen, Aachen, Germany

    Joachim Weis

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Contributions

J.B. and A.A. designed the study and wrote the manuscript. J.B., F.B., C.T., C.W., H.F., P.S., A.D.S., K.V.T. and J.W. did the experiments. J.B., F.B., C.T., C.W., H.F., A.D.S., K.V.T., K.-A.N., J.W. and A.A. analyzed the data.

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Correspondence to Adriano Aguzzi.

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Bremer, J., Baumann, F., Tiberi, C. et al. Axonal prion protein is required for peripheral myelin maintenance. Nat Neurosci 13, 310–318 (2010). https://doi.org/10.1038/nn.2483

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