Deficient Thyroid Hormone Transport to the Brain Leads to Impairments in Axonal Caliber and Oligodendroglial Differentiation

Background: 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. Methods: We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and MRI analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO). Findings: We have found that the MCT8-deficient subject presents severely reduced myelin lipid and protein staining and increased proportion of small-calibre myelinated axons in detriment of large-calibre ones. Mct8/Dio2 KO mice present myelination impairments and abnormal oligodendroglial development, both in proliferation and maturation. Interpretation: We conclude that the greater proportion of small-calibre axons and differentiation impairments in oligodendrocyte precursor cells arise as potential mechanisms underlying the permanent myelination defects in MCT8-deficiency. Moreover, we present the Mct8/Dio2 KO mouse model, and magnetic resonance imaging (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 of patients. Funding Statement: This study was supported by grants from the Spanish Plan Nacional de I+D+i (Grant No. SAF2017-86342-R), Consejo Superior de Investigaciones Cientificas (Grant No. 2020AEP044), the Sherman Foundation (Grant No. OTR02211) and the Asociacion Corriendo con el Corazon por Hugo (Grant No OTR06190). Declaration of Interests: The authors declare no competing financial interest exist. Ethics Approval Statement: Human studies: Tissue samples were collected and processed following the guidelines and approval by the ethics committee of our Institution (Consejo Superior de Investigaciones Cientificas, CSIC, permit number SAF2011-25608) and with written informed consent from the parents of all subjects, in agreement with the Declaration of Helsinki. The smallest possible number of samples was used to perform these studies and all personal data were treated anonymously. Animal studies: All experimental procedures involving animals were performed following the European Union Council guidelines (directive 2010/63/UE) and Spanish regulations (R.D. 53/2013) and were approved by the ethics committee Comite de Etica y Experimentacion Humana y Animal (CEEHA) at Consejo Superior de Investigaciones Cientificas (CSIC) and by the Comunidad Autonoma de Madrid Review Board (proex 162/17) for the use of animals for scientific purposes.