In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency.
Monocarboxylate transporter 8 (MCT8) transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome, comprising severe psychomotor retardation and elevated serum T3 levels. Because the neurological symptoms are most likely caused by a lack of TH transport into the central nervous system, the administration of a TH analog that does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism, and action both in vitro and in vivo. Incubation of SH-SY5Y neuroblastoma cells and MO3.13 oligodendrocytes with labeled substrates showed a time-dependent uptake of T3 and TA3. In intact SH-SY5Y cells, both T3 and TA3 were degraded by endogenous type 3 deiodinase, and they influenced gene expression to a similar extent. Fibroblasts from MCT8 patients showed an impaired T3 uptake compared with controls, whereas TA3 uptake was similar in patient and control fibroblasts. In transfected cells, TA3 did not show significant transport by MCT8. Most importantly, treatment of athyroid Pax8-knockout mice and Mct8/Oatp1c1-double knockout mice between postnatal days 1 and 12 with TA3 restored T3-dependent neural differentiation in the cerebral and cerebellar cortex, indicating that TA3 can replace T3 in promoting brain development. In conclusion, we demonstrated uptake of TA3 in neuronal cells and in fibroblasts of MCT8 patients and similar gene responses to T3 and TA3. This indicates that TA3 bypasses MCT8 and may be used to improve the neural status of MCT8 patients.
Department of Internal Medicine (S.K., W.E.V., E.C.H.F., R.P.P., T.J.V.) and Rotterdam Thyroid Center (S.K., W.E.V., R.P.P., T.J.V.), Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; Leibniz Institute for Age Research/Fritz Lipmann Institute (S.H., J.C., H.H.), Jena, Germany; Inserm (C.V.-B.), Unité Mixte de Recherche (UMR) 1103, and Centre National de la Recherche Scientifique (C.V.-B.), UMR6293, F-63001 Clermont-Ferrand, France; Clermont Université (C.V.-B.), Université d'Auvergne, Laboratoire GReD, BP 10448, F-63000 Clermont-Ferrand, France; and Leibniz Research Institute for Environmental Medicine (J.C., H.H.), Düsseldorf, Germany.
Simone
S
Kersseboom
Sigrun
S
Horn
W Edward
WE
Visser
Jiesi
J
Chen
Edith C H
EC
Friesema
Catherine
C
Vaurs-Barrière
Robin P
RP
Peeters
Heike
H
Heuer
Theo J
TJ
Visser
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins; D038901:X-Linked Intellectual Disability / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D009123:Muscle Hypotonia / Q000188:drug therapy* / Q000378:metabolism*; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D027981:Symporters; D014284:Triiodothyronine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use
D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C464433:Oatp2 protein, mouse; D027701:Organic Cation Transport Proteins; C090735:SLC16A2 protein, human; C484257:Slc16a2 protein, mouse; D027981:Symporters; D014284:Triiodothyronine; C010642:3,3',5-triiodothyroacetic acid