Defective thyroid hormone transport to the brain leads to astroglial alterations

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  • dc.contributor.author Guillén-Yunta, Marina
  • dc.contributor.author García-Aldea, Ángel
  • dc.contributor.author Valcárcel-Hernández, Víctor
  • dc.contributor.author Sanz-Bógalo, Ainara
  • dc.contributor.author Muñoz-Moreno, Emma
  • dc.contributor.author Matheus, Maria Gisele
  • dc.contributor.author Grijota-Martínez, Carmen
  • dc.contributor.author Montero-Pedrazuela, Ana
  • dc.contributor.author Guadaño-Ferraz, Ana
  • dc.contributor.author Bárez-López, Soledad
  • dc.date.accessioned 2025-11-24T07:03:27Z
  • dc.date.available 2025-11-24T07:03:27Z
  • dc.date.issued 2024
  • dc.description.abstract 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.en
  • dc.description.sponsorship This study was supported by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe” (Grants No. SAF2017–86342-R and PID2020-113139RB-I00 to AG-F), Consejo Superior de Investigaciones Científicas (Grant No. 2020AEP044 to AG-F), The Sherman Foundation (Grant No. OTR02211 to SB-L and AG-F), Asociación Corriendo con el Corazón por Hugo (Grant No. OTR06190 to AG-F), a contract from Ministerio de Ciencia, Innovación y Universidades (Programa de Formación de Profesorado (FPU, FPU19/02006) to MG-Y, a contract from Universidad Autónoma de Madrid (Contrato predoctoral para Formación de personal Investigador en Formación, FPI-UAM) to AG-A, a contract from MCIN/AEI/10.13039/501100011033 and “ESF Investing in your future” (Grant No. PRE2018–086185) to VV-H, and a grant from the MCIN/AEI/10.13039/501100011033 and the European Union NextGenerationEU/PRTR (Grant No. IJC2020–043543-I) to SB-L.en
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Guillén-Yunta M, García-Aldea Á, Valcárcel-Hernández V, Sanz-Bógalo A, Muñoz-Moreno E, Matheus MG, et al. Defective thyroid hormone transport to the brain leads to astroglial alterations. Neurobiol Dis. 2024 Oct 1;200:106621. DOI: 10.1016/j.nbd.2024.106621
  • dc.identifier.doi http://dx.doi.org/10.1016/j.nbd.2024.106621
  • dc.identifier.issn 0969-9961
  • dc.identifier.uri http://hdl.handle.net/10230/71972
  • dc.language.iso eng
  • dc.publisher Elsevier
  • dc.relation.ispartof Neurobiology of Disease. 2024 Oct 1;200:106621
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113139RB-I00
  • dc.rights © 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/bync/4.0/).
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/bync/4.0/
  • dc.subject.keyword Thyroid hormonesen
  • dc.subject.keyword Thyroid hormone transportersen
  • dc.subject.keyword MCT8en
  • dc.subject.keyword Astrogliaen
  • dc.subject.keyword MCT8 deficiencyen
  • dc.subject.keyword MRIen
  • dc.title Defective thyroid hormone transport to the brain leads to astroglial alterationsen
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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