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

• Applicants: Dr. Stefanie Albrecht; Dr. Petra Hundehege
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268918409

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.

• DFG Programme: Research Grants