Axonal prion protein is required for peripheral myelin maintenance.
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.
Bremer
Juliane
J
Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
Baumann
Frank
F
Tiberi
Cinzia
C
Wessig
Carsten
C
Fischer
Heike
H
Schwarz
Petra
P
Steele
Andrew D
AD
Toyka
Klaus V
KV
Nave
Klaus-Armin
KA
Weis
Joachim
J
Aguzzi
Adriano
A
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
D058851:GPI-Linked Proteins; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse