The role of the two pore-domain potassium channel TASK1 in oligodendroglial maturation and myelin regeneration

多发性硬化症（MS）是一种中枢神经系统的慢性自身免疫性疾病。脱髓鞘是MS病理学的显著标志，导致神经系统症状的轴突传导阻滞。在后期阶段，大量轴突和神经元损失，部分是髓鞘再生不足的结果，是解释已知MS病理学的同样重要的特征。在MS（实验性自身免疫性脑脊髓炎）动物模型中，抑制双孔结构域钾（K2 P）通道家族成员TASK 1可降低疾病严重程度，并能够降低脑实质体积的进行性损失。除了存在于神经元和免疫细胞上之外，TASK 1通道最近被证明也在少突胶质细胞上表达。然而，到目前为止，这些通道对MS中少突胶质细胞成熟以及髓鞘再生的调节的影响还没有研究。我们的初步数据表明，小鼠少突胶质细胞系的细胞表达功能TASK 1通道在体外。Task 1基因的消融显著地使静息膜电位去极化，降低增殖能力并促进髓鞘相关基因表达。此外，10日龄的Task 1-/-小鼠显示神经元轴突的髓鞘形成增加，脑中成熟少突胶质细胞的数量增加，而敲除和野生型动物之间未成熟和成熟少突胶质细胞的总数是无关紧要的。因此，TASK 1通道的功能障碍诱导从增殖的前体细胞到成熟的、产生髓鞘的少突胶质细胞的加速分化。这些发现表明TASK 1通道在调节少突胶质细胞的基本功能（增殖和分化）中发挥重要作用。因此，该研究的目的是更好地了解TASK 1在少突胶质细胞成熟中的作用，并质疑TASK 1通道是否是促进病理性髓鞘丢失后髓鞘再生的潜在治疗靶点。因此，我们将追求以下三个目标：（1）我们将分析调节TASK 1活性的上游信号传导以及影响鼠少突胶质细胞培养物的增殖和分化的TASK 1下游级联;（2）我们将在两种不同的动物模型中确定脱髓鞘后髓鞘修复期间TASK 1通道抑制的治疗效力;（3）我们将评估TASK 1在体外人少突胶质细胞和MS切片损伤区域的表达，以研究TASK 1通道功能障碍是否可能导致MS髓鞘再生失败。

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Demyelination is a striking hallmark of MS pathology leading to a conduction block of axons underlying neurological symptoms. At later stages substantial axonal and neuronal loss, partially the consequence of the failure of adequate myelin regeneration, are equally important features accounting for the known MS symptomatology. The inhibition of a member of the two-pore-domain potassium (K2P) channel family, TASK1, could be shown to reduce disease severity and was capable of lowering progressive loss of brain parenchymal volume in an animal model of MS (experimental autoimmune encephalomyelitis). Beside its presence on neurons and immune cells TASK1 channels were recently shown to be also expressed on oligodendroglial cells. However, the influence of these channels on the regulation of oligodendroglial maturation as well as remyelination in MS is not investigated so far. Our preliminary data demonstrate that cells of the murine oligodendroglial lineage express functional TASK1 channels in vitro. Ablation of the Task1 gene significantly depolarizes the resting membrane potential, reduces the proliferative capacity and promotes myelin associated gene expression. Furthermore, 10 days-old Task1-/- mice reveal increased myelination of neuronal axons and a higher number of mature oligodendrocytes in the brain while total numbers of immature and mature oligodendroglial cells are indifferent between knockout and wild type animals. Hence, a dysfunction of TASK1 channels induces an accelerated differentiation from proliferating precursor cells to mature, myelin-producing oligodendrocytes. These findings indicate a major role of TASK1 channels in the regulation of fundamental oligodendroglial cell functions: proliferation and differentiation. Hence, the aim of the study is to get a better understanding of the role of TASK1 in oligodendroglial maturation and to question whether TASK1 channels are potential treatment targets to promote remyelination after pathological myelin loss. Therefore, we will pursue the following three objectives: (1) we will analyse both upstream signalling that modulates TASK1 activity as well as cascades downstream of TASK1 that affect proliferation and differentiation of murine oligodendroglial cell culture; (2) we will determine the therapeutic potency of TASK1 channel inhibition during myelin repair after demyelination in two different animal models; and (3) we will evaluate TASK1 expression on human oligodendrocytes in vitro and in lesioned areas of MS sections to investigate whether a dysfunction of TASK1 channels might contribute to the remyelination failure in MS.