Journal Article

Axonal prion protein is required for peripheral myelin maintenance

Fischer, Heike, Toyka, Klaus V, Weis, Joachim, Steele, Andrew D, Baumann, Frank, Aguzzi, Adriano, Nave, Klaus-Armin, Tiberi, Cinzia, Bremer, Juliane, Wessig, Carsten, Schwarz, Petra

2010

Overview

The signals ensuring maintenance of the myelin sheath on peripheral nerves are distinct from those instructing myelination and are largely unknown. Here, the authors report that neuronal expression and regulated proteolysis of the prion protein are essential for 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/2606 / 631/45/460 / 692/698/1688/1959 / 692/699/375/430 / Ablation / Age / Alternative Splicing / Animal Genetics and Genomics / Animals / Axons - physiology / Axons - ultrastructure / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Chronic Disease / Degeneration / Demyelinating Diseases - metabolism / Demyelinating Diseases - pathology / Genetic aspects / GPI-Linked Proteins / Kinases / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Inbred Strains / Mice, Knockout / Mice, Transgenic / Morphology / Myelin Sheath - physiology / Myelin Sheath - ultrastructure / Nerve Fibers, Myelinated - physiology / Nerve Fibers, Myelinated - ultrastructure / Nervous system / Neurobiology / Neurodegeneration / Neurons / Neurons - physiology / Neurons - ultrastructure / Neuropathology / Neurosciences / Peripheral Nerves - physiology / Peripheral Nerves - ultrastructure / Physiological aspects / Polyneuropathies - metabolism / Polyneuropathies - pathology / Prions / Prions - genetics / Prions - metabolism / Proteins / PrPC Proteins - genetics / PrPC Proteins - metabolism / Schwann Cells - physiology / Schwann Cells - ultrastructure / Sciatic Nerve - metabolism / Sciatic Nerve - pathology