Papers

Theiler’s virus offers a remarkable example of a pathogen that navigates the various cells of the organism to evade immune responses and establish a persistent infection. Here, we discuss the transition from neuron to myelin and oligodendrocyte infection, a step that is crucial for the persistence of this virus in the central nervous system (CNS). CNS myelin is an extension of the cytoplasmic membrane of oligodendrocytes wrapped numerous times around axons. An oligodendrocyte sends many such extensions and can myelinate up to 50 different axons. Myelinated axon segments are separated by short unmyelinated
regions called nodes of Ranvier. 

Thyroid hormone is essential for proper brain development since it acts on processes such as neuronal migration and differentiation, myelination and synaptogenesis. In this review, we summarize the consequences of thyroid hormone deficiency for brain development with special focus on the cerebellum, an important target of thyroid action. In addition, we discuss the role of iodothyronine deiodinases and thyroid hormone transporters in regulating local thyroid hormone concentrations as well as current knowledge about the function of thyroid hormone receptors and their target genes during brain maturation.

Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of L-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice.

Mutations of the gene expressing plasma membrane transporter for thyroid hormones MCT8 (SLC16A2) in humans lead to altered thyroid hormone levels and a severe neurodevelopmental disorder. Genetically engineered defect of the Mct8 gene in mice leads to similar thyroid hormone abnormalities, but no obvious impairment of brain development or function. In this work we studied the relative role of the blood-brain barrier, and the neuronal plasma cell membrane in the restricted access of T3 to the target neurons. To this end we compared the effects of low doses of T4 and T3 on cerebellar structure and gene expression in wild type (Wt) and Mct8 null male mice (Mct8-/y, KO) made hypothyroid during the neonatal period. We found that compared to Wt animals, T4 was considerably more potent than T3 in the Mct8KO mice, indicating a restricted access of T3, but not T4, to neurons after systemic administration in vivo.

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function. Am J Physiol Heart Circ Physiol 296: H1551–H1557, 2009. First published March 13, 2009; doi:10.1152/ajpheart.01293.2008.— Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature,potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option.

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).

Pelizaeus–Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus–Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression.

W. Edward Visser,1 Jurgen Jansen,1 Edith C.H. Friesema,1 Monique H.A. Kester,1 Edna Mancilla,2 Johan Lundgren,3 Marjo S. van der Knaap,4 Roelineke J. Lunsing,5 Oebele F. Brouwer,5 and Theo J. Visser1 Abstract:  Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,30,5-triiodothyronine (T3). Mutations in MCT8 are associated with severe psychomotor retardation, […]

In hypothyroid patients, altered microvascular structure and function may affect mood and cognitive function. We hypothesized that adult male hypothyroid rats will have significantly lower forebrain blood vessel densities (BVD) than euthyroid rats and that treatment with 3,5- diiothyroprionic acid (DITPA) (a thyroid hormone analog) or thyroxine (T4) will normalize BVDs. The euthyroid group received no thyroidectomy or treatment. The other three groups received thyroidectomies and pellets. The hypothyroid group received a placebo pellet, the DITPA group received an 80-mg DITPA-containing pellet, and the T4 group received a 5.2-mg T4 slow-release pellet for 6 wk.

Context: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct Xlinked phenotype of severe psychomotor retardation and consistently elevated T3 levels. Lack of MCT8 transport of T3 in neurons could explain the neurological phenotype.

Objective: Our objective was to determine whether the high T3 levels could also contribute to some critical features observed in these patients.