Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish

Dis Model Mech. 2016 Nov 1;9(11):1339-1348. doi: 10.1242/dmm.027227. Epub 2016 Sep 23.


Hypomyelination is a key symptom of Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8 (monocarboxylate transporter 8). 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 compared with wild type. 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 TH-dependent brain disorders.

Keywords: Allan-Herndon-Dudley syndrome (AHDS); Blood–brain barrier; Live imaging; Mct8; Myelin; Psychomotor-retardation; Thyroid; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / pathology*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cell Count
  • Cell Differentiation / drug effects
  • Clemastine / pharmacology*
  • Gene Expression Regulation / drug effects
  • Genetic Therapy*
  • Larva / drug effects
  • Larva / genetics
  • Monocarboxylic Acid Transporters / deficiency
  • Monocarboxylic Acid Transporters / metabolism*
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology*
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism
  • Schwann Cells / drug effects
  • Schwann Cells / metabolism
  • Schwann Cells / pathology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Thyroid Hormones / agonists
  • Thyroid Hormones / metabolism
  • Zebrafish / genetics*


  • Biomarkers
  • Monocarboxylic Acid Transporters
  • Slc16a2 protein, zebrafish
  • Thyroid Hormones
  • Clemastine