School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, 3083, Australia.
Faculty of Applied Medical Sciences, Najran University, Najran, Saudi Arabia.
Sci Rep. 2020 Mar 6;10(1):4189. doi: 10.1038/s41598-020-60699-8.
Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs) in blood and cerebrospinal fluid. Previously, two reports identified TTR null mice as hypothyroid in the central nervous system (CNS). This prompted our investigations into developmentally regulated TH-dependent processes in brains of wildtype and TTR null mice. Despite logical expectations of a hypomyelinating phenotype in the CNS of TTR null mice, we observed a hypermyelination phenotype, synchronous with an increase in the density of oligodendrocytes in the corpus callosum and anterior commissure of TTR null mice during postnatal development. Furthermore, absence of TTR enhanced proliferation and migration of OPCs with decreased apoptosis. Neural stem cells (NSCs) isolated from the subventricular zone of TTR null mice at P21 revealed that the absence of TTR promoted NSC differentiation toward a glial lineage. Importantly, we identified TTR synthesis in OPCs, suggestive of an alternate biological function in these cells that may extend beyond an extracellular TH-distributor protein. The hypermyelination mechanism may involve increased pAKT (involved in oligodendrocyte maturation) in TTR null mice. Elucidating the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for the treatment of acquired demyelinating diseases.
转甲状腺素蛋白（TTR）是一种在血液和脑脊液中结合和分布甲状腺激素（THs）的蛋白质。此前，有两份报告指出 TTR 缺失的小鼠在中枢神经系统（CNS）中表现为甲状腺功能减退。这促使我们对野生型和 TTR 缺失的小鼠大脑中受 TH 调节的发育过程进行研究。尽管我们预期 TTR 缺失的小鼠中枢神经系统会出现脱髓鞘表型，但实际上我们观察到了一种超髓鞘化表型，与 TTR 缺失的小鼠在出生后发育过程中胼胝体和前连合中的少突胶质细胞密度增加同步。此外，TTR 的缺失增强了少突胶质前体细胞（OPC）的增殖和迁移，同时减少了其凋亡。我们从 TTR 缺失的小鼠侧脑室下区分离出的神经干细胞（NSC）表明，TTR 的缺失促进了 NSC 向神经胶质谱系的分化。重要的是，我们在 OPC 中鉴定出了 TTR 的合成，这表明 TTR 在这些细胞中具有除了作为细胞外 TH 分布蛋白之外的另一种生物学功能。TTR 缺失的小鼠中 pAKT（参与少突胶质细胞成熟）的增加可能与超髓鞘化机制有关。阐明 TTR 在 NSC 和 OPC 生物学中的调节作用可能为治疗获得性脱髓鞘疾病提供潜在的治疗策略。
