The thyroid hormone transporter monocarboxylate transporter 8 is required for normal CNS myelination in the human brain

Abstract

Mutations in the gene encoding the highly specific thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) produce an X-linked disease known as Allan-Herndon-Dudley Syndrome (AHDS), consisting of cognitive disability and motor disorders with abnormal serum TH levels. MRI shows delayed myelination in these patients but our recent neurohistopathological findings in the brain of two MCT8-deficient subjects indicate a myelination delay at 30 gestational weeks (gwk) and persistent hypomyelination (lower myelin lipid, protein content and density of myelinated axons) at 11 years of age in different brain regions. We aim to better understand the myelination defect in MCT8-deficient subjects during development and childhood. Given the relationship between axon diameter and myelination, we first analyzed the morphology and diameter of myelinated axons in several brainstem axonal tracts from autopsy tissue of the MCT8-deficient 11-year-old boy. For this we used the luxol fast blue technique (LFB) and immunohistochemistry for neurofilament-70kD (NEFL). As TH regulate oligodendrocyte generation we also characterized the normal cellular expression of MCT8 in the white matter at several fetal stages and the MCT8 expression in the MCT8-deficient fetal brain. LFB showed mainly low caliber myelinated axons with a lower proportion of large diameter myelinated axons in the MCT8-deficient boy (P< 0.0001). NEFL immunohistochemistry confirmed these results. We found that white matter MCT8 expression begins around 25 gwk in a large number of glial cells, and interestingly, a drastic increase was observed at 30 gwk. This high level was maintained at 38 gwk. MCT8 expression was confined to GFAP+ and Olig2+ cells, which correspond to astrocytes and oligodendrocytes precursors, and myelinating oligodendrocytes. However, the MCT8-deficient fetus did not express MCT8 in white matter glial cells. These results highlight the importance of TH local availability regulation by MCT8 in axonal growth and glial cells differentiation in the human brain.