Papers

How does thyroid hormone (TH) find its way into the brain? Although it has been known for a long time that this crucial for normal brain development, the exact molecular mechanisms involved in TH transport in the brain have remained elusive until recently. Early studies showed selective and saturable accumulation of TH in particular brain regions, suggesting that active transport processes are required forTHentry across the blood-brain barrier (BBB) and into brain cells (1). The discovery that TH transporter proteins located in the plasma membrane are required for cellular entry of the hormone has advanced our understanding of TH physiology. Thus, TH transporters mediate transport not only across the BBB but also into each individual cell of the brain.

The mechanism of thyroid hormone (TH) secretion from the thyroid gland into the blood is
unknown. We used the Mct8 deficient mouse (Mct8KO) to determine if MCT8 has a role in this
process. While MCT8 is known to transport TH into cells, several observations suggest that it also
controls TH secretion: (1) Humans and mice deficient in MCT8 have a low serum T4 level, which
cannot be fully explained by increased deiodination; (2) Our preliminary data show that TH
secretion in Mct8KO mice is delayed following the release of endogenous hormone suppression with
methimazole and perchlorate; (3) MCT8 is localized at the basolateral membrane of thyrocytes.
RESULTS: Thyroid glands of Mct8KO mice contained 2.1-fold and 2.3-fold more free T4 and T3 than
wild-type (Wt) mice (P<0.001). This was independent of deiodination as comparable increases were also found in Mct8KO mice that lacked the types 1 and 2 deiodinases.

This is the fourth newsletter in our series of newsletters on the AHDS or MCT8 deficiency. In this edition, you can read about the progress of the Triac Trial, the genetic basis of the AHDS and much more.

Hypomyelination is a key symptom of the Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8/-) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8-/- larvae and adults. Live imaging of single glial cells showed that the number of oligodendrocytes and the length of their extensions are reduced, and the number of peripheral Schwann cells is increased in mct8-/- larvae. Pharmacological analysis showed that TH analogs and clemastine partially rescued the hypomyelination in the CNS of mct8-/- larvae. Intriguingly, triiodothyronine (T3) treatment rescued hypomyelination in mct8-/- embryos before the maturation of the blood-brain barrier (BBB), but did not affect hypomyelination in older larvae. Thus, we expressed Mct8-tagRFP in the endothelial cells of the vascular system and showed that even relatively weak mosaic expression completely rescued hypomyelination in mct8/- larvae. These results suggest potential pharmacological treatments and BBB-targeted gene therapy that can enhance myelination in AHDS and possibly in other THdependent brain disorders.

MCT8 gene mutations produce thyroid hormone (TH) deficiency in the brain, causing severe neuropsychomotor abnormalities not correctable by treatment with TH. In this proof of concept study, we examined whether transfer of human MCT8 (hMCT8) cDNA using adeno-associated virus 9 (AAV9) could correct the brain defects of Mct8 knockout mice

The Allan-Herndon-Dudley syndrome (AHDS) is caused by a defect in the thyroid hormone (TH) transporter MCT8 (1,2). The clinical phenotype comprises a “central” component due to impaired psychomotor development with severe intellectual disability, axial hypotonia and dystonia, and a ‘’peripheral’’ component dominated by signs of thyrotoxicosis, caused by elevated serum T3 levels. The combination of high serum T3, low or low-normal serum (F)T4 and normal to modestly elevated serum TSH levels are very typical for AHDS

The evolutionary acquisition of myelin sheaths around large caliber axons in the central nervous system (CNS) represented a milestone in the development of vertebrate higher brain function. Myelin ensheathment of axons enabled salta-tory conduction and thus accelerated information processing. However, a number of CNS diseases harm or destroy myelin and oligodendrocytes (mye-lin-producing cells), ultimately resulting in demyelination. In the adult CNS, new oligodendrocytes can be generated from a quiescent pool of precursor cells, which – upon differentiation – can replace lost myelin sheaths. The efficiency of this spontaneous regeneration is limited, which leads to incomplete remyeli-nation and residual clinical symptoms. Here, we discuss CNS pathologies characterized by white matter degeneration and regeneration and highlight drugs that could potentially serve as remyelination therapies.

Methods
Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transmembrane transporter expressed in many cell types, including neurons. Mutations which inactivate transport activity of MCT8 cause severe X-linked psychomotor retardation in male patients, a syndrome originally described as the Allan-Herndon-Dudley syndrome. Treatment options currently explored focus on finding thyroid hormone-like compounds which bypass MCT8 and enter cells through different transporters. Since MCT8 is a multipass transmembrane protein, some pathogenic mutations affect membrane trafficking while potentially retaining some transporter activity.

Objective:
To test the hypothesis that circulating low T4 and high T3 levels are caused by enhanced conversion of T4 via increased activity of hepatic type I-deiodinase (Dio1).