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Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression.

Authors
  • Wilpert, Nina-Maria1
  • Krueger, Martin2
  • Opitz, Robert1
  • Sebinger, David1
  • Paisdzior, Sarah1
  • Mages, Bianca2
  • Schulz, Angela3
  • Spranger, Joachim4
  • Wirth, Eva K4
  • Stachelscheid, Harald5, 6
  • Mergenthaler, Philipp7, 8
  • Vajkoczy, Peter9
  • Krude, Heiko1
  • Kühnen, Peter1
  • Bechmann, Ingo2
  • Biebermann, Heike1
  • 1 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Experimental Pediatric Endocrinology, Berlin, Germany. , (Germany)
  • 2 Institute of Anatomy, University of Leipzig, Leipzig, Germany. , (Germany)
  • 3 Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, University of Leipzig, Leipzig, Germany. , (Germany)
  • 4 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology, Diabetes and Nutrition, Berlin, Germany. , (Germany)
  • 5 Stem Cell Core Facility, Berlin Institute of Health, Berlin, Germany. , (Germany)
  • 6 Charité - Universitätsmedizin Berlin, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany. , (Germany)
  • 7 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Experimental Neurology, Department of Neurology, Center for Stroke Research Berlin, Berlin, Germany. , (Germany)
  • 8 Berlin Institute of Health (BIH), Berlin, Germany. , (Germany)
  • 9 Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neurosurgery, Berlin, Germany. , (Germany)
Type
Published Article
Journal
Thyroid
Publisher
Mary Ann Liebert
Publication Date
Sep 01, 2020
Volume
30
Issue
9
Pages
1366–1383
Identifiers
DOI: 10.1089/thy.2019.0544
PMID: 32143555
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Background: Mutations of monocarboxylate transporter 8 (MCT8), a thyroid hormone (TH)-specific transmembrane transporter, cause a severe neurodevelopmental disorder, the Allan-Herndon-Dudley syndrome. In MCT8 deficiency, TH is not able to reach those areas of the brain where TH uptake depends on MCT8. Currently, therapeutic options for MCT8-deficient patients are missing, as TH treatment is not successful in improving neurological deficits. Available data on MCT8 protein and transcript levels indicate complex expression patterns in neural tissue depending on species, brain region, sex, and age. However, information on human MCT8 expression is still scattered and additional efforts are needed to map sites of MCT8 expression in neurovascular units and neural tissue. This is of importance because new therapeutic strategies for this disease are urgently needed. Methods: To identify regions and time windows of MCT8 expression, we used highly specific antibodies against MCT8 to perform immunofluorescence labeling of postnatal murine brains, adult human brain tissue, and human cerebral organoids. Results: Qualitative and quantitative analyses of murine brain samples revealed stable levels of MCT8 protein expression in endothelial cells of the blood-brain barrier (BBB), choroid plexus epithelial cells, and tanycytes during postnatal development. Conversely, the neuronal MCT8 protein expression that was robustly detectable in specific brain regions of young mice strongly declined with age. Similarly, MCT8 immunoreactivity in adult human brain tissue was largely confined to endothelial cells of the BBB. Recently, cerebral organoids emerged as promising models of human neural development and our first analyses of forebrain-like organoids revealed MCT8 expression in early neuronal progenitor cell populations. Conclusions: With respect to MCT8-deficient conditions, our analyses not only strongly support the contention that the BBB presents a lifelong barrier to TH uptake but also highlight the need to decipher the TH transport role of MCT8 in early neuronal cell populations in more detail. Improving the understanding of the spatiotemporal expression in latter barriers will be critical for therapeutic strategies addressing MCT8 deficiency in the future.

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