Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.
Tuning PAK Activity to Rescue Abnormal Myelin Permeability in HNPP.
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DOI：
10.1371/journal.pgen.1006290
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发表时间：
2016-09
期刊：
影响因子：
4.5
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Hu B;Arpag S;Zhang X;Möbius W;Werner H;Sosinsky G;Ellisman M;Zhang Y;Hamilton A;Chernoff J;Li J
周围神经系统中的雪旺细胞延伸其膜，同心包裹轴突，形成被称为髓鞘的绝缘鞘。髓鞘层之间的空隙被髓鞘连接所封闭。这种紧密的绝缘使电脉冲(动作电位)能够通过轴突快速传导。脱髓鞘(剥离绝缘鞘)被广泛认为是许多神经系统疾病中改变动作电位传播的最重要的机制之一。然而，有效的神经传导也被认为需要通过髓鞘连接(如紧密连接和粘连连接)进行适当的髓鞘封闭。在本研究中，我们证明了PMP22基因杂合性缺失的遗传性神经病(HNPP)小鼠模型(PMP22+/-)髓鞘连接的破坏。我们观察到，在髓鞘连接被破坏的PMP22+/-神经区，F-肌动蛋白显著增加，导致髓鞘通透性增加。这些异常在PMP22+/-小鼠晚期节段性脱髓鞘之前很久就出现了。此外，F-肌动蛋白水平的增加与p21-激活激酶(PAK1)活性的增强有关，PAK1是一种已知的调节肌动蛋白聚合的分子。PAK的药物抑制使F-肌动蛋白水平正常化，并完全阻止了PMP22+/-小鼠髓鞘连接断裂和神经传导障碍的进展。我们的发现解释了HNPP中髓鞘通透性异常是如何引起的，导致在没有脱髓鞘的情况下动作电位传播受损。我们称之为“功能性脱髓鞘”，这是一种位于髓鞘实际剥离上游的新机制，与许多脱髓鞘疾病有关。这一观察也为HNPP提供了一种潜在的治疗方法。在许多神经系统疾病中，脱髓鞘被广泛认为是影响电脉冲神经传导的重要机制之一。神经传导障碍会导致感觉和运动障碍。在目前的研究中，我们研究了一种新的机制，即功能性脱髓鞘，这种机制也可以在不去除髓鞘的情况下损害神经传导。PMP22基因两个拷贝之一的缺失会导致遗传性神经病，并易患压力性瘫痪(HNPP)。我们最近的研究报道，HNPP中PMP22的缺失破坏了雪旺细胞的髓鞘连接，该连接封闭了髓鞘膜层之间的间隙。这种破坏会导致髓鞘“泄漏”，从而损害神经上电脉冲的传导。在目前的研究中，使用HNPP小鼠模型(PMP22+/-)，我们已经确定了导致髓鞘连接中断的分子途径。我们的结果显示，在髓鞘连接所在的区域，肌动蛋白聚合增加。这种增加与PAK1活性的上调有关，PAK1是一种已知的调节肌动蛋白聚合的激酶功能。因此，我们用PAK1抑制剂对HNPP小鼠进行治疗。这种治疗完全阻止了神经传导衰竭和HNPP病理的进展。这项工作为HNPP提供了一种有前途的治疗方法。此外，髓鞘连接的破坏发生在HNPP晚期髓鞘实际剥离(脱髓鞘)之前很久。因此，我们的发现为节段性脱髓鞘提供了一种上游机制，节段性脱髓鞘是与许多脱髓鞘疾病相关的病理过程。
Schwann cells in the peripheral nervous systems extend their membranes to wrap axons concentrically and form the insulating sheath, called myelin. The spaces between layers of myelin are sealed by myelin junctions. This tight insulation enables rapid conduction of electric impulses (action potentials) through axons. Demyelination (stripping off the insulating sheath) has been widely regarded as one of the most important mechanisms altering the action potential propagation in many neurological diseases. However, the effective nerve conduction is also thought to require a proper myelin seal through myelin junctions such as tight junctions and adherens junctions. In the present study, we have demonstrated the disruption of myelin junctions in a mouse model (Pmp22+/-) of hereditary neuropathy with liability to pressure palsies (HNPP) with heterozygous deletion of Pmp22 gene. We observed a robust increase of F-actin in Pmp22+/- nerve regions where myelin junctions were disrupted, leading to increased myelin permeability. These abnormalities were present long before segmental demyelination at the late phase of Pmp22+/- mice. Moreover, the increase of F-actin levels correlated with an enhanced activity of p21-activated kinase (PAK1), a molecule known to regulate actin polymerization. Pharmacological inhibition of PAK normalized levels of F-actin, and completely prevented the progression of the myelin junction disruption and nerve conduction failure in Pmp22+/- mice. Our findings explain how abnormal myelin permeability is caused in HNPP, leading to impaired action potential propagation in the absence of demyelination. We call it “functional demyelination”, a novel mechanism upstream to the actual stripping of myelin that is relevant to many demyelinating diseases. This observation also provides a potential therapeutic approach for HNPP. Demyelination has been widely regarded as one of the most important mechanisms impairing the nerve conduction of electrical impulses in many neurological diseases. Failure of the nerve conduction results in sensory and motor deficits. In the present study, we investigated a novel mechanism that also impairs nerve conduction without the removal of myelin, called functional demyelination. Deletion of one of two copies of the PMP22 gene causes hereditary neuropathy with liability to pressure palsies (HNPP). Our recent study reports that deficiency of PMP22 in HNPP disrupts myelin junctions of Schwann cells that seal the spaces between layers of myelin membrane. This disruption leads to “leaky” myelin that impairs the conduction of electrical impulses on the nerves. In the present study, using a HNPP mouse model (Pmp22+/-), we have identified a molecular pathway responsible for the disruption of myelin junctions. Our results showed an increase of actin polymerization in the areas where myelin junctions resided. This increase was associated with an up-regulation of PAK1 activity, a kinase function that is known to regulate actin polymerization. We thus treated the HNPP mice with PAK1 inhibitor. This treatment completely prevented the progression of nerve conduction failure and HNPP pathology. This work offers a promising therapeutic approach for HNPP. Moreover, myelin junction disruption takes place long before the actual stripping of myelin (demyelination) in the late phase of HNPP. Therefore, our finding provides a mechanism upstream to segmental demyelination, a pathological process relevant to many demyelinating diseases.
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三个紧密连接相关的Maguks ZO-1，ZO-2和ZO-3与Claudins的Cooh Termini直接结合。
DOI：
10.1083/jcb.147.6.1351
发表时间：
1999-12-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Itoh M;Furuse M;Morita K;Kubota K;Saitou M;Tsukita S
通讯作者：
Tsukita S
影响因子：
4
作者：
Chies, R;Nobbio, L;Brancolini, C
通讯作者：
Brancolini, C
影响因子：
5.3
作者：
Boda, B;Alberi, S;Muller, D
通讯作者：
Muller, D
影响因子：
11.2
作者：
Chow HY;Jubb AM;Koch JN;Jaffer ZM;Stepanova D;Campbell DA;Duron SG;O'Farrell M;Cai KQ;Klein-Szanto AJ;Gutkind JS;Hoeflich KP;Chernoff J
通讯作者：
Chernoff J
影响因子：
6.1
作者：
Notterpek, L;Ryan, MC;Shooter, EM
通讯作者：
Shooter, EM