RT Journal Article
T1 Defective thyroid hormone transport to the brain leads to astroglial alterations
A1 Guillén Yunta, Marina
A1 García Aldea, Ángel
A1 Valcárcel Hernández, Víctor
A1 Sanz Bógalo, Ainara
A1 Muñoz Moreno, Emma
A1 Matheus, Maria Gisele
A1 Grijota Martínez, María Carmen
A1 Montero Pedrazuela, Ana
A1 Guadaño Ferraz, Ana
A1 Bárez López, Soledad
AB 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.
PB Elsevier
SN 0969-9961
YR 2024
FD 2024
LK https://hdl.handle.net/20.500.14352/117657
UL https://hdl.handle.net/20.500.14352/117657
LA eng
NO Guillén-Yunta, M., García-Aldea, Á., Valcárcel-Hernández, V., Sanz-Bógalo, A., Muñoz-Moreno, E., Matheus, M. G., Grijota-Martínez, C., Montero-Pedrazuela, A., Guadaño-Ferraz, A., & Bárez-López, S. (2024). Defective thyroid hormone transport to the brain leads to astroglial alterations. Neurobiology of Disease, 200, 106621. https://doi.org/10.1016/j.nbd.2024.106621
NO 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.
NO Ministerio de Ciencia e Innovación (España)
NO European Commission
NO The Sherman Foundation
NO Asociación Corriendo con el Corazón por Hugo
NO Universidad Autónoma de Madrid
DS Docta Complutense
RD 21 abr 2025