Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels
Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels
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DOI：
10.1007/s00401-007-0333-3
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发表时间：
2008-05-01
影响因子：
12.7
通讯作者：
Suzuki, Kinuko
中科院分区：
文献类型：
--
作者：
Kagitani-Shimono, Kuriko;Mohri, Ikuko;Suzuki, Kinuko
由遗传性半乳糖神经酰胺酶缺乏引起的球形细胞脑白质营养不良（GLD;克拉伯病）影响中枢和外周神经系统（CNS和PNS）。异基因造血干细胞移植（HSCT）对改善本病的临床疗效有积极意义。然而，Siddiqi等人最近的报告表明，他们的移植患者中没有一个实现了外周神经功能的完全正常化，尽管在治疗的患者中CNS和PNS的髓鞘再生得到了充分的证明。我们假设GLD中的PNS功能障碍是由于雪旺氏细胞-轴突相互作用的改变，导致Ranvier结的结构异常和脱髓鞘引起的离子通道的异常表达，并且这种改变的相互作用的持续性是HSCT后PNS功能障碍的原因。由于还没有任何调查的雪旺氏细胞轴突的关系，在抽搐小鼠，一个真实的模型，GLD，我们首先调查结构异常，集中在节点的Ranvier在未经处理的抽搐小鼠，并比较结果与接受骨髓移植（BMT）后获得的。正如预期的那样，我们发现了许多多余的雪旺细胞，形成结构异常的朗维尔节点。在用BMT处理的小鼠中检测到类似的结果，尽管程度有所不同。激活的额外雪旺细胞表达GFAP免疫反应性，并产生阿新蓝阳性细胞外基质（ECM）在神经内膜空间。这些多余的雪旺氏细胞的突起经常覆盖和消除结区。此外，Na+通道免疫反应性的分布是弥漫性的，而没有在野生型小鼠中观察到的朗维尔结处的浓度。在twi/twi坐骨神经中未检测到K+通道或Neurexin IV/ Caspr/ Paranoidin（NCP-1）。我们的研究结果表明，正常化的雪旺细胞轴突的关系，周围神经的功能恢复的重要性，当一个考虑治疗策略PNS病理学在GLD。
Globoid cell leukodystrophy (GLD; Krabbe's disease), caused by a genetic galactosylceramidase deficiency, affects both the central and peripheral nervous systems (CNS and PNS). Allogenic hematopoietic stem-cell transplantation (HSCT) has been beneficial for clinical improvement of this disease. However, recent reports by Siddiqi et al. suggested that none of their transplanted patients achieved complete normalization of their peripheral nerve function, despite the well-documented remyelination of the CNS and PNS in the treated patients. We hypothesized that the PNS dysfunction in GLD is due to altered Schwann cell-axon interactions, resulting in structural abnormalities of the node of Ranvier and aberrant expression of ion channels caused by demyelination and that the persistence of this altered interaction is responsible for the dysfunction of the PNS after HSCT. Since there has not been any investigation of the Schwann cell-axonal relationship in twitcher mice, an authentic model of GLD, we first investigated structural abnormalities, focusing on the node of Ranvier in untreated twitcher mice, and compared the results with those obtained after receiving bone marrow transplantation (BMT). As expected, we found numerous supernumerary Schwann cells that formed structurally abnormal nodes of Ranvier. Similar findings, though at somewhat variable extent, were detected in mice treated with BMT. Activated supernumerary Schwann cells expressed GFAP immunoreactivity and generated Alcian blue-positive extracellular matrix (ECM) in the endoneurial space. The processes of these supernumerary Schwann cells often covered and obliterated the nodal regions. Furthermore, the distribution of Na+ channel immunoreactivity was diffuse without the concentration at the nodes of Ranvier as seen in wild-type mice. Neither K+ channels nor Neurexin IV/ Caspr/ Paranoidin (NCP-1) were detected in the twi/twi sciatic nerve. The results of our study suggest the importance of normalization of the Schwann cell-axon relationship for the functional recovery of peripheral nerves, when one considers therapeutic strategies for PNS pathology in GLD.