Oligodendroglial Lineage Cells in Thyroid Hormone-Deprived Conditions

Abstract

Oligodendrocytes are supporting glial cells that ensure the metabolism and homeostasis of neurons with specific synaptic axoglial interactions in the central nervous system. These require key myelinating glial trophic signals important for growth and metabolism. Thyroid hormone (TH) is one such trophic signal that regulates oligodendrocyte maturation, myelination, and oligodendroglial synaptic dynamics via either genomic or nongenomic pathways. The intracellular and extracellular transport of TH is facilitated by a specific transmembrane transporter known as the monocarboxylate transporter 8 (MCT8). Dysfunction of the MCT8 due to mutation, inhibition, or downregulation during brain development leads to inherited hypomyelination, which manifests as psychomotor retardation in the X-linked inherited Allan-Herndon-Dudley syndrome (AHDS). In particular, oligodendroglial-specific MCT8 deficiency may restrict the intracellular T₃ availability, culminating in deficient metabolic communication between the oligodendrocytes and the neurons they ensheath, potentially promulgating neurodegenerative adult diseases such as multiple sclerosis (MS). Based on the therapeutic effects exhibited by TH in various preclinical studies, particularly related to its remyelinating potential, TH has now entered the initial stages of a clinical trial to test the therapeutic efficacy in relapsing-remitting MS patients (NCT02506751). However, TH analogs, such as DITPA or Triac, may well serve as future therapeutic options to rescue mature oligodendrocytes and/or promote oligodendrocyte precursor cell differentiation in an environment of MCT8 deficiency within the CNS. This review outlines the therapeutic strategies to overcome the differentiation blockade of oligodendrocyte precursors and maintain mature axoglial interactions in TH-deprived conditions.

Figure 1

Hypothyroid state within the CNS leads to cellular hypothyroidism in oligodendrocytes. In the euthyroid state, functional MCT8 expressed on oligodendrocyte precursors (OPCs) is able to transport thyroid hormone (T₃) across the plasma membrane promoting their differentiation and maturation. Normal myelination subsequently occurs. When MCT8 is dysfunctional due to various points or frameshift mutations, or in the context of neuroinflammation, intracellular T₃ transport is impeded, as a result of dysfunctional MCT8. This results in a profound hypothyroid state in OPCs, leading to their stalled differentiation, or indeed apoptosis, with the eventual neurobiological result being hypomyelination and the clinical outcome being neurodegeneration and cognitive decline.

Figure 2

The expression of MCT8 in human oligodendrocytes and its altered expression pattern in secondary progressive MS. Immunofluorescent images illustrating (a) the axonal and oligodendroglial expression of MCT8 in nonneurological disease control (NNDC) brain tissue. (b) Secondary progressive MS cerebellar white matter stained with Luxol fast blue with periodic acid Schiff (LFB/PAS) demonstrating chronic demyelinated lesions (light purple in the center) and with Bielschowsky silver stain demonstrating axonal loss and degeneration. Immunofluorescent images illustrating (c) apoptotic Olig2+ oligodendroglial lineage cells, and (d) apoptotic oligodendrocytes expressing MCT8 in secondary progressive multiple sclerosis cerebellar white matter (outlined in the box in (b)).