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

Fredrik S Skedsmo,Arild Espenes,Michael A Tranulis,Kaspar Matiasek,Gjermund Gunnes,Inge Bjerkås,Lars Moe,Susan Skogtvedt Røed,Mette Berendt,Merete Fredholm,Cecilia Rohdin,G Diane Shelton,Per Bruheim,Marit H Stafsnes,Zdenka Bartosova,Lene C Hermansen,Øyvind Stigen,Karin H Jäderlund

doi:10.1016/j.nmd.2020.11.010

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-Marie-Tooth 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.

Highlights

Humans, classified as Charcot-Marie-Tooth type 4D (CMT4D) [1], Greyhound show dogs [2] and Alaskan Malamute dogs [3]
The N-myc downstream-regulated gene 1 (NDRG1)-associated polyneuropathy of Greyhound show dogs was reportedly dominated by axonal changes [2], while descriptions from Alaskan Malamutes are differing [3, 4]
Since NDRG1 is expressed in Schwann cells and not axons, polyneuropathies associated with mutations in NDRG1 are expected to result from compromised Schwann cell functions

Summary

Introduction

Humans, classified as Charcot-Marie-Tooth type 4D (CMT4D) [1], Greyhound show dogs [2] and Alaskan Malamute dogs [3]. The NDRG1 protein is not specific for peripheral nerves and is detected in a wide variety of human, rodent and dog tissues with the highest levels in epithelial cells and myelinating glial cells [6,7,8]. Charcot-Marie-Tooth disease (CMT) denominates the most frequent forms of inherited neuropathies in humans. This is a heterogeneous group of diseases, further classified into subtypes based on clinical and pathological phenotype, mode of inheritance, nerve conduction velocity and causative gene [21]. Dogs share environmental conditions and lifestyle with humans Together this makes them excellent translational disease models [2]. Studying Alaskan Malamutes with a NDRG1 mutation is relevant to understand more about the involvement of NDRG1 in human diseases

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