Defective thyroid hormone transport to the brain leads to astroglial alterations

Abstract

Background: 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. Methods: We conducted magnetic resonance imaging on both control subjects and MCT8-deficient patients to examine changes in brain cytoarchitecture. Moreover, to gain further understanding on these alterations in brain cytoarchitecture and the astroglial population, we have performed histological and immunohistochemical approaches in autopsy brain samples from an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. Findings from MCT8-deficient subjects were validated and further explored in a mouse model of the AHDS. Results: Magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients. Further studies confirmed changes in the astroglial population in MCT8 deficiency that arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, and morphology of cortical astrocytes, compatible with an astrogliosis-like phenotype at adult stages. Conclusions: We have identified astrocytes as potential novel therapeutic targets in AHDS. In addition, we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.