A Mouse Model of Schwartz-Jampel Syndrome Reveals Myelinating Schwann Cell Dysfunction with Persistent Axonal Depolarization in Vitro and Distal Peripheral Nerve Hyperexcitability When Perlecan Is Lacking
A Mouse Model of Schwartz-Jampel Syndrome Reveals Myelinating Schwann Cell Dysfunction with Persistent Axonal Depolarization in Vitro and Distal Peripheral Nerve Hyperexcitability When Perlecan Is Lacking
复制标题
DOI：
10.1016/j.ajpath.2012.01.035
复制
发表时间：
2012-05-01
影响因子：
6
通讯作者：
Nicole, Sophie
中科院分区：
文献类型：
--
作者：
Bangratz, Marie;Sarrazin, Nadege;Nicole, Sophie
先天性周围神经高兴奋性(PNH)通常与神经肌张力的电压门控性钾通道(VGKCs)功能受损和周围神经病的脱髓鞘有关。Schwartz-Jampel综合征(SJS)是PNH的一种，是由于基底膜的主要蛋白多糖Perlecan亚型突变所致。雪旺细胞基底膜及其细胞受体对兰维尔结节的髓鞘形成和组织至关重要。因此，我们研究了SJS的小鼠模型，以确定当缺乏Perlecan时，Perlecan在这些功能中的作用是否可以解释PNH。我们揭示了Perlecan在髓鞘雪旺细胞的纵向伸长和组织中的作用，因为Perlecan缺陷的小鼠有更短的节间，更多的Schmidt-Lanterman切牙，以及节间快速VGKC的数量增加。Perlecan缺乏的小鼠并没有表现出沿着神经主干的脱髓鞘事件，但在神经肌肉接头处出现了与去神经过程相关的终末前段的髓鞘异常。对周围神经兴奋性特性的研究表明，在体外神经放电过程中，轴突去极化持续存在，很可能是由于K+稳态的缺陷，并排除了神经干作为PNH的原始部位。总之，我们的数据揭示了Perlecan在雪旺细胞生理学中的关键作用，并表明SJS中的PNH远端起源于周围神经和神经肌肉接头变化的协同作用。(Am J Pathol2012,1802040年-2055年；DOI：10.1016/j.ajpath.2012.01.035)
Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K+ channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K+ homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes. (Am J Pathol 2012, 180: 2040-2055; DOI: 10.1016/j.ajpath.2012.01.035)