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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.

Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan–Herndon–Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments. The impact of MCT8 deficiency in the neurosensory capacity of AHDS patients is less clear, with only a few patients displaying visual and auditory impairments. In this review we aim to gather data from different animal models regarding thyroid hormone transport and action in the different neurosensory systems that could aid to identify potential neurosensorial alterations in MCT8-deficient patients.

Objectives: The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release. Methods: We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland. Results: We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis. Conclusion: In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.

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. We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and magnetic resonance imaging (MRI) analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO). We have found that the MCT8-deficient subject presents severely reduced myelin lipid and protein staining and increased proportion of small-caliber myelinated axons in detriment of large-caliber ones. Mct8/Dio2 KO mice present myelination impairments and abnormal oligodendroglial development. We conclude that the greater proportion of small-caliber axons and impairments in the oligodendroglia lineage progression arise as potential mechanisms underlying the permanent myelination defects in MCT8-deficiency. Moreover, we present the Mct8/Dio2 KO mouse model, and 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 in patients.

Allan-Herndon-Dudley syndrome is a rare disease caused by inactivating mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8), a transmembrane transporter specific for thyroid hormones (T3 and T4). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development resulting in severe brain hypothyroidism. Patients also suffer from thyrotoxicity in other organs due to the presence of a high concentration of T3 in the serum. An effective therapeutic strategy should restore thyroid hormone serum levels (both T3 and T4) and should address MCT8 transporter deficiency in brain barriers and neural cells, to enable the access of thyroid hormones to target neural cells. Unfortunately, targeted therapeutic options are currently scarce and their effect is limited to an improvement in the thyrotoxic state, with no sign of any neurological improvement. The use of thyroid hormone analogs such as TRIAC, DITPA, or sobetirome, that do not require MCT8 to cross cell membranes and whose controlled thyromimetic activity could potentially restore the normal function of the affected organs, are being explored to improve the cerebral availability of these analogs. Other strategies aiming to restore the transport of THs through MCT8 at the brain barriers and the cellular membranes include gene replacement therapy and the use of pharmacological chaperones. The design of an appropriate therapeutic strategy in combination with an early diagnosis (at prenatal stages), will be key aspects to improve the devastating alterations present in these patients.

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.

Patients lacking the thyroid hormone (TH) transporter MCT8 present abnormal serum levels of TH: low thyroxine and high triiodothyronine. They also have severe neurodevelopmental defects resulting from cerebral hypothyroidism, most likely due to impaired TH transport across the brain barriers. The use of TH analogs, such as triiodothyroacetic acid (TRIAC), that can potentially access the brain in the absence of MCT8 and restore at least a subset of cerebral TH actions could improve the neurological defects in these patients. We hypothesized that direct administration of TRIAC into the brain by intracerebroventricular delivery to mice lacking MCT8 could bypass the restriction at the brain barriers and mediate TH action without causing hypermetabolism. We found that intracerebroventricular administration of therapeutic doses of TRIAC does not increase further plasma triiodothyronine or further decrease plasma thyroxine levels and does not alter TH content in the cerebral cortex. Although TRIAC content increased in the brain, it did not induce TH-mediated actions on selected target genes. Our data suggest that intracerebroventricular delivery of TRIAC has the ability to target the brain in the absence of MCT8 and should be further investigated to address its potential therapeutic use in MCT8 deficiency.

Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.

BackgroundThyroid hormones have a key role in both the developing and adult central nervous system and skeletal muscle. The thyroid gland produces mainly thyroxine (T4) but the intracellular concentrations of 3,5,3'-triiodothyronine (T3; the transcriptionally active hormone) in the central nervous system and skeletal muscle are modulated by the activity of type 2 deiodinase (D2). To date no neurological syndrome has been associated with mutations in the DIO2 gene and previous studies in young and juvenile D2-knockout mice (D2KO) did not find gross neurological alterations, possibly due to compensatory mechanisms.AimThis study aims to analyze the motor phenotype of 3-and-6-month-old D2KO mice to evaluate the role of D2 on the motor system at adult stages in which compensatory mechanisms could have failed.ResultsMotor abilities were explored by validated tests. In the footprint test, D2KO showed an altered global gait pattern (mice walked slower, with shorter strides and with a hindlimb wider base of support than wild-type mice). No differences were detected in the balance beam test. However, a reduced latency to fall was found in the rotarod, coat-hanger and four limb hanging wire tests indicating impairment on coordination and prehensile reflex and a reduction of muscle strength. In histological analyses of cerebellum and skeletal muscle, D2KO mice did not present gross structural abnormalities. Thyroid hormones levels and deiodinases activities were also determined. In D2KO mice, despite euthyroid T3 and high T4 plasma levels, T3 levels were significantly reduced in cerebral cortex (48% reduction) and skeletal muscle (33% reduction), but not in the cerebellum where other deiodinase (type 1) is expressed.ConclusionsThe motor alterations observed in D2KO mice indicate an important role for D2 in T3 availability to maintain motor function and muscle strength. Our results suggest a possible implication of D2 in motor disorders.