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表位标记的P(0)糖蛋白在转基因小鼠中引发了类夏科-马里-图斯病性神经病。

Epitope-tagged P(0) glycoprotein causes Charcot-Marie-Tooth-like neuropathy in transgenic mice.

作者信息

Previtali S C, Quattrini A, Fasolini M, Panzeri M C, Villa A, Filbin M T, Li W, Chiu S Y, Messing A, Wrabetz L, Feltri M L

机构信息

Department of Neurology and Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, 20132 Milan, Italy.

出版信息

J Cell Biol. 2000 Nov 27;151(5):1035-46. doi: 10.1083/jcb.151.5.1035.

DOI:10.1083/jcb.151.5.1035
PMID:11086005
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2174348/
Abstract

In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P(0)) glycoprotein. Point mutations in this region of P(0) cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P(0) modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P(0)myc retained partial adhesive function, and suggested that the transgene inhibits P(0)-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P(0) ECD mutants and the normal interactions of P(0) in the myelin sheath.

摘要

在周围神经髓鞘中，主周期线是由于蛋白零（P(0)）糖蛋白的细胞外结构域（ECD）之间的嗜同性粘附导致细胞外空间压缩而形成的。P(0)这个区域的点突变会导致人类遗传性脱髓鞘性神经病，如夏科-马里-图斯病。我们描述了表达在ECD中用myc表位标签修饰的全长P(0)的转基因小鼠。myc序列的存在导致了一种脱髓鞘性周围神经病，类似于夏科-马里-图斯病的两种不同亚型，表现为髓鞘形成不足、主周期线改变和髓鞘瘤（髓鞘增厚）。带标签的蛋白质被整合到髓鞘中，并与形态学异常有关。体内和体外实验表明，P(0)myc保留了部分粘附功能，并提示转基因以显性负性方式抑制P(0)介导的粘附。这些小鼠揭示了P(0) ECD突变体发病机制以及P(0)在髓鞘中正常相互作用的新机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/84ce/2174348/34d55524d1c5/JCB0007139.f7.jpg
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