Axonal prion protein is required for peripheral myelin maintenance.

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Axonal prion protein is required for peripheral myelin maintenance.

..T .Bremer1, F. Baumann1, C. Tiberi1, P. Schwarz1, C. Wessig2

, A.D. Steele3 , K,V.Toyka2, K-A. Nave4,.T. Weiss and A. Aguzzi1

lInstitute of Neuropathology, University Hospital of Zurich, Zurich,

Switzerland; 2Department of Neurology, University of Wurzburg, Wurzburg,

Germany; 'Division of Biology, California Institute of Technology, Pasadena CA,

USA; 4Department of Neurogenetics, Max-Planck Institute of Experimental

Medicine, Gottingen, Germany; 'Institute of Neuropathology, Medical Faculty,

RWTH University Aachen, Aachen, Germany

The integrity of peripheral nerves relies on messaging between axons and Schwann

cells. The axonal signals ensuring myelin maintenance are distinct from those

instructing myelination, and are largely unknown Here we show that ablation of

the prion protein, Prpc, triggers a

chronic demyelinating polyneuropathy (CDP) in three independently targeted mouse

strains.

Ablation of the neighboring Prnd locus, or inbreeding to four distinct mouse

strains, did not modulate the CDP Unexpectedly, CDP was triggered by

neuron-specific Prpc depletion and was suppressed by neuronal, but not by

Schwann-cell restricted, Prpc expression.

Therefore, expression of Prpc by neurons is necessary and sufficient for myelin

maintenance. All Prpc variants undergoing proteolytic amino proximal cleavage

prevented the CDP, but none of those nonpermissive for cleavage, including

soluble Prpc lacking the glycolipid anchor.

These results suggest that regulated proteolysis of axonal Prpc liberates

myelinotrophic fragments which act in trans on the adaxonal surface of myelin

sheaths.