title: Axonal prion protein is required for peripheral myelin maintenance.
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 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.
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bremer
authors.forename: Frank
authors.initials: F
authors.lastname: Baumann
authors.forename: Cinzia
authors.initials: C
authors.lastname: Tiberi
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Heike
authors.initials: H
authors.lastname: Fischer
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Steele
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D058851:GPI-Linked Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009413:Nerve Fibers, Myelinated / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000502:physiology* / Q000648:ultrastructure; D011115:Polyneuropathies / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000502:physiology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology
chemical_list: D058851:GPI-Linked Proteins; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse