Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development

Valcarcel-Hernandez, Victor; Lopez-Espindola, Daniela; Guillen-Yunta, Marina; Garcia-Aldea, Angel; de Toledo Soler, Ines Lopez; Barez-Lopez, Soledad; Guadano-Ferraz, Ana

Abstract

Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to profound brain alterations, including myelination impairments, in humans. We aimed to further explore the pathophysiological mechanisms underlying the MCT8 deficiency-associated myelination impairments to unravel new biomarkers and therapeutic targets. We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and magnetic resonance imaging (MRI) analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO). We have found that the MCT8deficient subject presents severely reduced myelin lipid and protein staining and increased proportion of smallcaliber myelinated axons in detriment of large-caliber ones. Mct8/Dio2 KO mice present myelination impairments and abnormal oligodendroglial development. We conclude that the greater proportion of small-caliber axons and impairments in the oligodendroglia lineage progression arise as potential mechanisms underlying the permanent myelination defects in MCT8-deficiency. Moreover, we present the Mct8/Dio2 KO mouse model, and MRI as a non-invasive biomarker, as highly valuable tools for preclinical studies involving MCT8 deficiency. These findings contribute to the understanding of the pathological mechanisms in MCT8 deficiency and suggest new biomarkers and therapeutic targets to consider therapeutic options for the neurological defects in patients.

Más información

Título según WOS: Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development
Título de la Revista: NEUROBIOLOGY OF DISEASE
Volumen: 162
Editorial: ACADEMIC PRESS INC ELSEVIER SCIENCE
Fecha de publicación: 2022
DOI:

10.1016/j.nbd.2021.105567

Notas: ISI