Pathophysiology of MCT8 deficiencyStudies in humans and mice

Resumen

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disease caused by mutations in the gene SLC16A2 that encodes the monocarboxylate transporter 8 (MCT8), a transmembrane protein highly specific for the transport of thyroid hormones (TH). This syndrome is characterized by peripheral thyrotoxicosis, cerebral hypothyroidism most likely due to a restriction in the transport of TH across brain barriers, and severe neurological disorders. However, the pathophysiology of AHDS is not well known, and there is currently no effective treatment for the severe neurological damage observed in patients. The work in this thesis has been carried out using data and brain tissue from subjects with MCT8 deficiency, as well as using an animal model of the disease, the Mct8/Dio2KO mice. The aim of the thesis is to deepen our understanding of the pathophysiology of the disease and to validate an animal model for its use as a tool in preclinical studies. In the study of human brain tissue, we have found the presence of astrogliosis and microgliosis in the cerebral cortex of a subject with MCT8 deficiency. In contrast, in the basal ganglia of this same subject we observed a decrease in glial cell density and expression of astroglial and microglial markers. We have also furthered understanding of the pathophysiology of neuronal function by finding alterations in specific markers of synapses, myelin and mitochondria. Using brain magnetic resonance imaging (MRI) in patients diagnosed with AHDS, we detected an increase in the apparent diffusion coefficient (ADC) in the basal ganglia and hippocampus. These results highlight the usefulness of MRI as a non-invasive tool, both in the diagnosis and in the follow-up of the disease and its treatments, as well as the potential usefulness of ADC measurement as a new biomarker of the disease. The 3 and 6-month-old Mct8/Dio2KO mice also showed signs of astro- and microgliosis in the cerebral cortex, although without relevant changes in the synaptic and mitochondrial markers compared to control animals. Mct8/Dio2KO mice also showed important alterations in markers of dopaminergic and GABAergic pathways in the basal ganglia. On the other hand, given the importance of astrocytes in the integrity of the blood-brain barrier (BBB) and the high expression of MCT8 in this structure, possible alterations in BBB permeability were explored, finding an increase in IgG extravasation in the brain of Mct8/Dio2KO animals. As in patients, we found alterations in the ADC measurement in the brain of these mice, as well as signs of brain atrophy. Finally, metabolic studies have shown an increase in energy expenditure associated with a phenotype of hyperactivity in the Mct8/Dio2KO animals and alterations in the concentration of the brain metabolites choline and N-acetylaspartate