Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brains

Wang, T.; Wang, Yu; Montero-Pedrazuela, Ana; Prensa, Lucı́a; Guadaño-Ferraz, Ana; Rausell, Estrella

doi:10.3390/ijms24119643

Cited by 2 publications

(1 citation statement)

References 91 publications

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“…In recent years, a growing number of evidence has been gathered that indeed points to the basal ganglia as an important CNS structure underlying AHDS pathophysiology. MCT8 protein expression was recently found in MSNs in the human striatum, suggesting a direct function of this TH transporter within the basal ganglia circuits [38]. Moreover, MRI studies have detected lesions in the putamen in MCT8 deficiency [39,40].…”

Section: Discussionmentioning

confidence: 98%

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

Siemes,

Vancamp,

Markova

et al. 2023

Cells

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Thyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong central TH deprivation, locomotor impairments and similar histo-morphological features as seen in MCT8 patients. The pathways that cause these neuro-motor symptoms are poorly understood. In this paper, we performed proteome analysis of brain sections comprising cortical and striatal areas of 21-day-old WT and DKO mice. We detected over 2900 proteins by liquid chromatography mass spectrometry, 67 of which were significantly different between the genotypes. The comparison of the proteomic and published RNA-sequencing data showed a significant overlap between alterations in both datasets. In line with previous observations, DKO animals exhibited decreased myelin-associated protein expression and altered protein levels of well-established neuronal TH-regulated targets. As one intriguing new candidate, we unraveled and confirmed the reduced protein and mRNA expression of Pde10a, a striatal enzyme critically involved in dopamine receptor signaling, in DKO mice. As altered PDE10A activities are linked to dystonia, reduced basal ganglia PDE10A expression may represent a key pathogenic pathway underlying human MCT8 deficiency.

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Section: Discussionmentioning

confidence: 98%

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

Siemes,

Vancamp,

Markova

et al. 2023

Cells

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Defective thyroid hormone transport to the brain leads to astroglial alterations

Guillén-Yunta,

García-Aldea,

Valcárcel-Hernández

et al. 2024

Preprint

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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.

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Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brains

Cited by 2 publications

References 91 publications

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

Defective thyroid hormone transport to the brain leads to astroglial alterations

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