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Novel insights into the neurological pathophysiology of MCT8-deficiency

AuthorsGuillen-Yunta, M.; García-Aldea, A.; Valcárcel-Hernández, Victor; Grijota Martínez, María del Carmen; Guadaño-Ferraz, Ana
Issue Date4-Sep-2019
CitationX Reunión de la Red Glial Española (2019)
AbstractThyroid hormones (TH) are essential in the development of the brain, regulating processes such as the differentiation of neural cells and myelination. TH are secreted to the blood from the thyroid gland, mainly as T4, which in the brain is converted in the astrocytes into T3, the nuclear active form, by the enzyme deiodinase type 2 (DIO2). The Allan-Herndon-Dudley Syndrome (AHDS or MCT8 deficiency) is an X-linked rare disease caused by mutations in the monocarboxilate transporter 8 (MCT8), a transmembrane transporter specific for TH. AHDS is characterized by altered serum TH levels and severe neurological damage including profound psychomotor impairment. Evidences strongly suggest that the neurological syndrome in MCT8 deficiency is mainly due to cerebral hypothyroidism, since TH access across brain barriers is impaired. Mct8-deficient mice replicate the alterations in circulating TH levels but not the neurological syndrome observed in AHDS patients, due to a compensatory mechanism involving the Dio2 enzyme. This led us to characterize the neurological phenotype of the double Mct8/Dio2 knockout mouse (KO) to validate it as a possible model of the disease. Previous results from brain samples of an 11-year-old MCT8-deficient subject diagnosed with AHDS showed a severely altered expression of neuronal proteins, together with a delay in myelination. The goal of this work was to analyse glial populations and myelination in Mct8 absence in mice. To this aim, we used postnatal day 21 (P21) and P90 Mct8/Dio2KO mice as an animal model for Mct8 deficiency. Our results suggest a neuroinflammatory state in Mct8/Dio2KO mice. Evidences suggest that the lack of TH in Mct8/Dio2KO mice brain alters the development of neuroglial cells, which could lead to the sustained neuroinflammatory state observed. Myelin studies were also consistent with human data, showing low and aberrant myelination in Mct8/Dio2KO mice at P21 that is not fully reversed at P90.
DescriptionTrabajo presentado en la X Reunión de la Red Glial Española, celebrada en Santiago de Compostela (España) el 4 de septiembre de 2019.
Appears in Collections:(IIBM) Comunicaciones congresos
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