Department of Neurological Diseases and Aging, Instituto de Investigaciones Biomédicas Sols-Morreale, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Magnetic Imaging Resonance Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Neurobiol Dis. 2024 Oct 1;200:106621. doi: 10.1016/j.nbd.2024.106621. Epub 2024 Aug 2.
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 by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
Allan-Herndon-Dudley 综合征（AHDS）是一种罕见的 X 连锁疾病，可导致严重的神经损伤，目前尚无有效的治疗方法。AHDS 是由于甲状腺激素转运蛋白 MCT8 的失活突变引起的，该突变可阻止甲状腺激素进入大脑，导致脑甲状腺功能减退。然而，AHDS 的病理生理学仍不完全清楚，这对于开发治疗策略至关重要。基于表明甲状腺激素缺乏会导致星形胶质细胞改变的证据，包括星形胶质细胞增生，在这项工作中，我们通过磁共振成像、组织学、超微结构和免疫组织化学技术，以及挖掘可用的 RNA 测序结果，评估了 MCT8 缺乏症中的星形胶质细胞损伤。与对照组（n=11）相比，磁共振成像获得的表观扩散系数（ADC）成像值表明 MCT8 缺陷患者的脑细胞结构发生了改变。在 11 岁和 30 孕周 MCT8 缺陷患者的尸检脑样本中，通过针对星形胶质细胞标志物的免疫组织化学证实了星形胶质细胞改变，与相似年龄的对照组脑样本相比。在 AHDS 的小鼠模型中验证并进一步探讨了这些发现。我们的发现证实了 MCT8 缺陷中所有大脑皮质星形胶质细胞群体的变化，这些变化影响星形胶质细胞的代谢和线粒体细胞呼吸功能。这些损伤在大脑发育早期出现，并在成年期持续存在，揭示了皮质星形胶质细胞的异常分布、密度和形态，以及改变的转录组，与成年期的星形胶质细胞增生样表型一致。我们得出结论，星形胶质细胞是 AHDS 的潜在新治疗靶点，我们提出 ADC 成像作为监测 MCT8 缺乏症中神经损伤进展和潜在治疗效果的工具。
