Kazuya Kuboyama, Akihiro Fujikawa, Ryoko Suzuki, Masaharu Noda
Division of Molecular Neurobiology, National Institute for Basic Biology, and.
Division of Molecular Neurobiology, National Institute for Basic Biology, and School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Okazaki, Aichi 444-8787, Japan
J Neurosci. 2015 Sep 2;35(35):12162-71. doi: 10.1523/JNEUROSCI.2127-15.2015.
Multiple sclerosis (MS) is a progressive neurological disorder associated with myelin destruction and neurodegeneration. Oligodendrocyte precursor cells (OPCs) present in demyelinated lesions gradually fail to differentiate properly, so remyelination becomes incomplete. Protein tyrosine phosphatase receptor type Z (PTPRZ), one of the most abundant protein tyrosine phosphatases expressed in OPCs, is known to suppress oligodendrocyte differentiation and maintain their precursor cell stage. In the present study, we examined the in vivo mechanisms for remyelination using a cuprizone-induced demyelination model. Ptprz-deficient and wild-type mice both exhibited severe demyelination and axonal damage in the corpus callosum after cuprizone feeding. The similar accumulation of OPCs was observed in the lesioned area in both mice; however, remyelination was significantly accelerated in Ptprz-deficient mice after the removal of cuprizone. After demyelination, the expression of pleiotrophin (PTN), an inhibitory ligand for PTPRZ, was transiently increased in mouse brains, particularly in the neurons involved, suggesting its role in promoting remyelination by inactivating PTPRZ activity. In support of this view, oligodendrocyte differentiation was augmented in a primary culture of oligodendrocyte-lineage cells from wild-type mice in response to PTN. In contrast, these cells from Ptprz-deficient mice showed higher oligodendrocyte differentiation without PTN and differentiation was not enhanced by its addition. We further demonstrated that PTN treatment increased the tyrosine phosphorylation of p190 RhoGAP, a PTPRZ substrate, using an established line of OPCs. Therefore, PTPRZ inactivation in OPCs by PTN, which is secreted from demyelinated axons, may be the mechanism responsible for oligodendrocyte differentiation during reparative remyelination in the CNS.
Multiple sclerosis (MS) is an inflammatory disease of the CNS that destroys myelin, the insulation that surrounds axons. Associated damages to oligodendrocytes (the cells that produce myelin) and nerve fibers produce neurological disability. Most patients with MS have an initial relapsing-remitting course for 5-15 years. Remyelination during the early stages of the disease process has been documented; however, the molecular mechanism underlying remyelination has not been understood. Protein tyrosine phosphatase receptor type Z (PTPRZ) is a receptor-like protein tyrosine phosphatase preferentially expressed in the CNS. This study shows that pleiotrophin, an inhibitory ligand for PTPRZ, is transiently expressed and released from demyelinated neurons to inactivate PTPRZ in oligodendrocyte precursor cells present in the lesioned part, thereby allowing their differentiation for remyelination.
多发性硬化症（MS）是一种与髓鞘破坏和神经退行性变相关的进行性神经疾病。脱髓鞘病变中存在的少突胶质前体细胞（OPC）逐渐无法正常分化，因此髓鞘再生变得不完全。蛋白酪氨酸磷酸酶Z型受体（PTPRZ）是在OPC中表达最丰富的蛋白酪氨酸磷酸酶之一，已知其可抑制少突胶质细胞分化并维持其前体细胞阶段。在本研究中，我们使用铜螯合剂诱导的脱髓鞘模型研究了体内髓鞘再生的机制。喂食铜螯合剂后，Ptprz基因缺陷型和野生型小鼠在胼胝体中均表现出严重的脱髓鞘和轴突损伤。在两只小鼠的病变区域均观察到类似的OPC积累；然而，去除铜螯合剂后，Ptprz基因缺陷型小鼠的髓鞘再生明显加速。脱髓鞘后，多效生长因子（PTN），一种PTPRZ的抑制性配体，在小鼠脑中短暂增加表达，特别是在相关神经元中，这表明其通过使PTPRZ失活来促进髓鞘再生的作用。支持这一观点的是，野生型小鼠少突胶质细胞系细胞的原代培养中，PTN可增强少突胶质细胞的分化。相比之下，则Ptprz基因缺陷型小鼠的这些细胞在没有PTN的情况下显示出更高的少突胶质细胞分化，并且添加PTN后分化并未增强。我们进一步证明，使用已建立的OPC系，PTN处理可增加PTPRZ底物p190 RhoGAP的酪氨酸磷酸化。因此，脱髓鞘轴突分泌的PTN使OPC中的PTPRZ失活，可能是中枢神经系统修复性髓鞘再生过程中少突胶质细胞分化的机制。
多发性硬化症（MS）是一种中枢神经系统的炎症性疾病，会破坏围绕轴突的髓鞘绝缘层。少突胶质细胞（产生髓鞘的细胞）和神经纤维的相关损伤会导致神经功能障碍。大多数MS患者在5至15年的时间里经历最初的复发缓解病程。疾病过程早期的髓鞘再生已有记录；然而，髓鞘再生的分子机制尚未明确。蛋白酪氨酸磷酸酶Z型受体（PTPRZ）是一种优先在中枢神经系统中表达的受体样蛋白酪氨酸磷酸酶。本研究表明，多效生长因子（PTN），一种PTPRZ的抑制性配体，在脱髓鞘神经元中短暂表达并释放，以失活病变部位存在的少突胶质前体细胞中的PTPRZ，从而使其分化以进行髓鞘再生。
