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.

中文翻译：

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Schwann 细胞中 NDRG1 功能受损导致 Charcot-Marie-Tooth 4D 型狗模型中的脱髓鞘神经病变

N-myc 下游调节基因 1 (NDRG1) 中的突变导致退行性多发性神经病，其方式尚不清楚。我们调查了阿拉斯加雪橇犬的 NDRG1 错义突变引起的神经病变。在受影响的动物中，NDRG1 蛋白的神经水平降低了 70% 以上（p < 0.03）。神经纤维的髓鞘很薄，大的有髓纤维的损失很明显，梳理的纤维制剂显示脱髓鞘和髓鞘再生。含有肌动蛋白的丝状物质的内含物存在于 adaxonal Schwann 细胞质和 Schmidt-Lanterman 裂隙中。这种情况非常类似于人类 Charcot-Marie-Tooth 4D 型。然而，在本研究中发现的带有轴突内折叠分离轴突的局灶性折叠髓鞘是人类疾病中未描述的超微结构变化。此外，脂质组学分析揭示了外周神经脂质的严重损失。我们的数据表明，低水平的突变 NDRG1 不足以支持雪旺细胞维持髓鞘稳态。