PUBLICATION

Pharmacological and BBB-targeted genetic therapies for thyroid hormone-dependent hypomyelination

Authors
Zada, D., Tovin, A., Lerer-Goldshtein, T., Appelbaum, L.
ID
ZDB-PUB-160925-3
Date
2016
Source
Disease models & mechanisms   9(11): 1339-1348 (Journal)
Registered Authors
Appelbaum, Lior, Tovin, Adi, Zada, David
Keywords
Psychomotor-retardation, Live imaging, Zebrafish, Myelin, Thyroid, Mct8, Blood–brain barrier, Allan-Herndon-Dudley syndrome (AHDS)
MeSH Terms
  • Oligodendroglia/drug effects
  • Oligodendroglia/metabolism
  • Spinal Cord/drug effects
  • Spinal Cord/metabolism
  • Spinal Cord/pathology
  • Genetic Therapy*
  • Thyroid Hormones/agonists
  • Thyroid Hormones/metabolism
  • Schwann Cells/drug effects
  • Schwann Cells/metabolism
  • Schwann Cells/pathology
  • Animals
  • Cell Differentiation/drug effects
  • Stem Cells/drug effects
  • Stem Cells/metabolism
  • Biomarkers/metabolism
  • Blood-Brain Barrier/drug effects
  • Blood-Brain Barrier/pathology*
  • Larva/drug effects
  • Larva/genetics
  • Myelin Sheath/metabolism*
  • Myelin Sheath/pathology*
  • Gene Expression Regulation/drug effects
  • Clemastine/pharmacology*
  • Cell Count
  • Zebrafish/genetics*
  • Monocarboxylic Acid Transporters/deficiency
  • Monocarboxylic Acid Transporters/metabolism*
  • Brain/drug effects
  • Brain/metabolism
  • Brain/pathology
(all 31)
PubMed
27664134 Full text @ Dis. Model. Mech.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (3 images)
Show all Figures
Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
EGFPbiu10Tgstandard conditionsProtruding-mouthIFL
EGFPbiu3Tg; biu9Tg; ck1Tgstandard conditionsProtruding-mouthIFL
EGFPbiu9Tg; ck1Tg; mde4Tgstandard conditionsDays 7-13IFL
EGFPck1Tgstandard conditionsDay 4IFL
EGFPck1Tgstandard conditionsDay 6IFL
EGFPck1Tgstandard conditionsDays 14-20IFL
EGFPck1Tgstandard conditionsDays 7-13IFL
EGFPck1Tgstandard conditionsDay 6IFL
EGFPck1Tgstandard conditionsDay 4IFL
EGFPck1Tgstandard conditionsDays 7-13IFL
1 - 10 of 37
Show
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment by environment: 3,3',5-triiodo-L-thyronineDays 7-13
slc16a2biu4/biu4standard conditionsProtruding-mouth
slc16a2biu4/biu4standard conditionsProtruding-mouth
slc16a2biu4/biu4standard conditionsProtruding-mouth
slc16a2biu4/biu4standard conditionsProtruding-mouth
slc16a2biu4/biu4standard conditionsDay 4
slc16a2biu4/biu4standard conditionsDay 4
slc16a2biu4/biu4standard conditionsDay 4
slc16a2biu4/biu4standard conditionsDays 7-13
slc16a2biu4/biu4standard conditionsAdult
1 - 10 of 35
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
biu3TgTransgenic Insertion
    biu4
      		Small Deletion
      biu9TgTransgenic Insertion
        biu10TgTransgenic Insertion
          ck1TgTransgenic Insertion
            mde4TgTransgenic Insertion
              um13TgTransgenic Insertion
                1 - 7 of 7
                Show
                Human Disease / Model
                Human Disease Fish Conditions Evidence
                Allan-Herndon-Dudley syndromeslc16a2biu4/biu4; ck1TgcontrolIC
                1 - 1 of 1
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                Sequence Targeting Reagents
                No data available
                Fish
                Fish
                biu3Tg; biu9Tg; ck1Tg
                biu9Tg; ck1Tg; mde4Tg
                biu10Tg
                ck1Tg
                slc16a2biu4/biu4
                slc16a2biu4/biu4; ck1Tg
                WT
                1 - 7 of 7
                Show
                Antibodies
                No data available
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                DsRedxEFGDsRedx
                EGFPEFGEGFP
                GAL4EFGGAL4
                TagRFPEFGTagRFP
                1 - 4 of 4
                Show
                Mapping
                No data available
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                Citation
                Zada, D., Tovin, A., Lerer-Goldshtein, T., Appelbaum, L. (2016) Pharmacological and BBB-targeted genetic therapies for thyroid hormone-dependent hypomyelination. Disease models & mechanisms. 9(11):1339-1348.