Defective thyroid hormone transport to the brain leads to astroglial alterations.
1. Neurobiol Dis. 2024 Oct 1;200:106621. doi: 10.1016/j.nbd.2024.106621. Epub 2024 Aug 2. Defective thyroid hormone transport to the brain leads to astroglial alterations. Guillén-Yunta M(1), García-Aldea Á(1), Valcárcel-Hernández V(1), Sanz-Bógalo A(1), Muñoz-Moreno E(2), Matheus MG(3), Grijota-Martínez C(4), Montero-Pedrazuela A(5), Guadaño-Ferraz A(6), Bárez-López S(7). Author information: (1)Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain. (2)Magnetic Imaging Resonance Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. (3)Department of Radiology and Radiological Science, Medical University of South Carolina, Charleston, SC, USA. (4)Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain; Department of Cell Biology, Faculty of Biology, Universidad Complutense de Madrid, Madrid, Spain. (5)Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain. Electronic address: amontero@iib.uam.es. (6)Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain. Electronic address: ana.guadano.ferraz@csic.es. (7)Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain. Electronic address: sbarez@iib.uam.es. Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency. Copyright © 2024. Published by Elsevier Inc. DOI: 10.1016/j.nbd.2024.106621 PMID: 39097035 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare that they have no competing interests.