The role of transthyretin in oligodendrocyte maturation

Transthyretin (TTR) is a protein that binds and distributes thyroid hormones (THs). While TTR has long been known to be synthesised in the liver and in the choroid plexus of the brain, recent investigation have revealed that it is also synthesised by different neuronal cells, such as neurons, astrocytes, transit amplifying cells and Schwann cells. To the best of our knowledge, the roles of TTR synthesised by these neuronal cells have not yet been clearly elucidated. The TTR synthesised by the choroid plexus has a role in moving THs from the blood to the brain and in distributing THs in the cerebrospinal fluid. Previously two reports suggested that TTR null mice were hypothyroid in the central nervous system compared with wild-type mice. Therefore, we decided to investigate a well-characterised TH-dependent process in the brains of wild type and TTR null mice: the maturation of oligodendrocyte precursor cells into oligodendrocytes that myelinate axons of neurons in the corpus callosum and anterior commissure of the brain. Accordingly, four different age groups were chosen (P7, P14, P21 and weeks) to investigate key time points for oligodendrocyte maturation in the brains of wild type and TTR null mice. Interestingly, in complete contrast to what we expected, we observed hypermyelination in the brains of the TTR null mice during development. This hypermyelination phenotype was synchronous with a substantial increase in the density of oligodendrocytes in the medial area of the corpus callosum and in the anterior commissure during development from P7 until 12 weeks of age. Thus, we studied the maturation of oligodendrocyte precursor cells (OPCs) isolated from the cortices of P7 and E18 mouse brains. Interestingly, we found that the absence of TTR enhanced the proliferation and migration of the OPCs, as well as decreased the rate of apoptosis and affected the progression of the OPC cycle. Furthermore, the NSCs isolated from the subventricular zone of P21 TTR null mice showed that the absence of TTR promoted NSC differentiation into glial lineages. We have also shown, for the first time, that oligodendrocytes synthesise TTR, and the TTR synthesised by OPCs is not secreted. This is in contrast to TTR synthesised by the liver and choroid plexus (which is secreted). Taken together, these data indicate that TTR has a role in the regulation of myelination; where the absence of TTR accelerates NSC and OPC maturation and enhances myelination. Therefore, We hypothesised that endogenous TTR, which has been shown to be synthesised by OPCs, holds T4 in the cytosol of the cells; this controls the level of T4 available for deiodinated to T3, the functional form of THs. Elucidation the mechanism of the regulatory role of TTR in NSC and OPC biology could lead to potential therapeutic strategies for treatment of demyelination disease such as Multiple Sclerosis