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Research article - Peer-reviewed, 2021

Impaired NDRG1 functions in Schwann cells cause demyelinating neuropathy in a dog model of Charcot-Marie-Tooth type 4D

Skedsmo, Fredrik S.; Espenes, Arild; Tranulis, Michael A.; Matiasek, Kaspar; Gunnes, Gjermund; Bjerkas, Inge; Moe, Lars; Roed, Susan Skogtvedt; Berendt, Mette; Fredholm, Merete; Rohdin, Cecilia; Shelton, G. Diane; Bruheim, Per; Stafsnes, Marit H.; Bartosova, Zdenka; Hermansen, Lene C.; Stigen, Oyvind; Jaderlund, Karin H.

Abstract

Mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause degenerative polyneuropathy in ways that are poorly understood. We have investigated Alaskan Malamute dogs with neuropathy caused by a missense mutation in NDRG1. In affected animals, nerve levels of NDRG1 protein were reduced by more than 70% (p < 0.03). Nerve fibers were thinly myelinated, loss of large myelinated fibers was pronounced and teased fiber preparations showed both demyelination and remyelination. Inclusions of filamentous material containing actin were present in adaxonal Schwann cell cytoplasm and Schmidt-Lanterman clefts. This condition strongly resembles the human Charcot-MarieTooth type 4D. However, the focally folded myelin with adaxonal infoldings segregating the axon found in this study are ultrastructural changes not described in the human disease. Furthermore, lipidomic analysis revealed a profound loss of peripheral nerve lipids. Our data suggest that the low levels of mutant NDRG1 is insufficient to support Schwann cells in maintaining myelin homeostasis. (C) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license.

Keywords

Alaskan Malamute; Canine; CMT; Greyhound; N-myc downstream-regulated gene 1; Polyneuropathy

Published in

Neuromuscular Disorders
2021, Volume: 31, number: 1, pages: 56-68
Publisher: PERGAMON-ELSEVIER SCIENCE LTD

    UKÄ Subject classification

    Clinical Science

    Publication identifier

    DOI: https://doi.org/10.1016/j.nmd.2020.11.010

    Permanent link to this page (URI)

    https://res.slu.se/id/publ/110635