SH3TC2, a Protein Mutant in Charcot-Marie-Tooth Neuropathy, Links Peripheral Nerve Myelination to Endosomal Recycling

Authors

Claudia Stendel, ETH Zürich, Zürich, Switzerland
Andreas Roos, RWTH Aachen University, Aachen, Germany
Henning Kleine, RWTH Aachen University, Aachen, Germany
Estelle Arnaud, University of Lausanne, Lausanne, Switzerland
Murat Ozçelik, ETH Zürich, Zürich, Switzerland
Páris N. M. Sidiropoulos, ETH Zürich, Zürich, Switzerland
Jennifer Zenker, University of Lausanne, Lausanne, Switzerland
Fanny Schüpfer, University of Lausanne, Lausanne, Switzerland
Ute Lehmann, RWTH Aachen University, Aachen, Germany
Radoslaw M. Sobota, University of Southern Denmark, Odense, Denmark
David W. Litchfield, The University of Western OntarioFollow
Bernhard Lüscher, RWTH Aachen University, Aachen, Germany
Roman Chrast, University of Lausanne, Lausanne, Switzerland
Ueli Suter, ETH Zürich, Zürich, Switzerland
Jan Senderek, ETH Zürich, Zürich, Switzerland

Document Type

Article

Publication Date

8-2010

Journal

Brain

Volume

133

Issue

8

First Page

2462

Last Page

2474

URL with Digital Object Identifier

http://dx.doi.org/10.1093/brain/awq168

Abstract

Patients with Charcot-Marie-Tooth neuropathy and gene targeting in mice revealed an essential role for the SH3TC2 gene in peripheral nerve myelination. SH3TC2 expression is restricted to Schwann cells in the peripheral nervous system, and the gene product, SH3TC2, localizes to the perinuclear recycling compartment. Here, we show that SH3TC2 interacts with the small guanosine triphosphatase Rab11, which is known to regulate the recycling of internalized membranes and receptors back to the cell surface. Results of protein binding studies and transferrin receptor trafficking are in line with a role of SH3TC2 as a Rab11 effector molecule. Consistent with a function of Rab11 in Schwann cell myelination, SH3TC2 mutations that cause neuropathy disrupt the SH3TC2/Rab11 interaction, and forced expression of dominant negative Rab11 strongly impairs myelin formation in vitro. Our data indicate that the SH3TC2/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.