Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development

Valcárcel-Hernández, Víctor; López-Espíndola, Daniela; Guillen-Yunta, M.; García-Aldea, A.; Soler, Inés López de Toledo; Bárez-López, Soledad; Guadaño-Ferraz, Ana

doi:10.1016/j.nbd.2021.105567

Cited by 12 publications

(13 citation statements)

References 37 publications

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“…Our non-invasive translational MRI study revealed severe impairments of brain structure and function on a systems-level in Mct8/Oatp1c1 DKO mice, an animal model for AHDS. Previous histomorphological studies already described persistent myelination deficits and disturbed marker expression in cortical GABAergic interneurons, thereby replicating pathophysiological findings observed in patients’ derived brain sections [ 6 , 22 , 23 ]. Moreover, MRI studies have repeatedly reported myelination deficits in the AHDS brain although it is still a matter of debate whether MCT8 patients display a delayed or permanent hypomyelination [ 27 ].…”

Section: Discussionsupporting

confidence: 67%

“…Morphological abnormalities including aberrant myelination, grey matter atrophy and altered cortical interneuron marker expression as seen in MCT8 patients and Mct8/Oatp1c1 DKO mice [ 6 , 22 , 23 ] may form the structural basis for the neuropsychiatric abnormalities in patients. How these alterations translate into impaired whole-brain network function and subsequently affect behavioral outcome remains largely unknown.…”

Section: Resultsmentioning

confidence: 99%

“…DKO mice [6,22,23] may form the structural basis for the neuropsychiatric abnormalities in patients. How these alterations translate into impaired whole-brain network function and subsequently affect behavioral outcome remains largely unknown.…”

Section: Morphological Abnormalities Including Aberrant Myelination G...mentioning

confidence: 99%

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TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

Reinwald

Weber‐Fahr

Cosa‐Linan

et al. 2022

IJMS

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Dysfunctions of the thyroid hormone (TH) transporting monocarboxylate transporter MCT8 lead to a complex X-linked syndrome with abnormal serum TH concentrations and prominent neuropsychiatric symptoms (Allan-Herndon-Dudley syndrome, AHDS). The key features of AHDS are replicated in double knockout mice lacking MCT8 and organic anion transporting protein OATP1C1 (Mct8/Oatp1c1 DKO). In this study, we characterize impairments of brain structure and function in Mct8/Oatp1c1 DKO mice using multimodal magnetic resonance imaging (MRI) and assess the potential of the TH analogue 3,3′,5-triiodothyroacetic acid (TRIAC) to rescue this phenotype. Structural and functional MRI were performed in 11-weeks-old male Mct8/Oatp1c1 DKO mice (N = 10), wild type controls (N = 7) and Mct8/Oatp1c1 DKO mice (N = 13) that were injected with TRIAC (400 ng/g bw s.c.) daily during the first three postnatal weeks. Grey and white matter volume were broadly reduced in Mct8/Oatp1c1 DKO mice. TRIAC treatment could significantly improve white matter thinning but did not affect grey matter loss. Network-based statistic showed a wide-spread increase of functional connectivity, while graph analysis revealed an impairment of small-worldness and whole-brain segregation in Mct8/Oatp1c1 DKO mice. Both functional deficits could be substantially ameliorated by TRIAC treatment. Our study demonstrates prominent structural and functional brain alterations in Mct8/Oatp1c1 DKO mice that may underlie the psychomotor deficiencies in AHDS. Additionally, we provide preclinical evidence that early-life TRIAC treatment improves white matter loss and brain network dysfunctions associated with TH transporter deficiency.

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Section: Discussionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

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TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

Reinwald

Weber‐Fahr

Cosa‐Linan

et al. 2022

IJMS

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“…Given that thyroid hormone has been shown to be important for hypothalamic parvalbumin neuron development ( Mittag et al, 2013 ), we were surprised that the vast majority of other hypothalamic neurons were not obviously affected in TRα1+m mice. The massive defect in oligodendrocyte development, by contrast, was not too unexpected given the well-established role of thyroid hormone in this context in other brain regions, as evidenced by severe white matter abnormalities in children with untreated congenital hypothyroidism ( Perri et al, 2021 ) or individuals with Allan–Herndon–Dudley syndrome, a disorder characterized by severely impaired thyroid hormone import into the brain ( Valcárcel-Hernández et al, 2022 ). Similar observations have been made in other species, such as zebrafish ( Farías-Serratos et al, 2021 ) or rats ( Barradas et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-based phenotyping reveals a pivotal role of thyroid hormone receptor alpha for hypothalamic development

et al. 2023

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Thyroid hormone and its receptor TRα1 play an important role in brain development. Several animal models have been used to investigate this function, including mice heterozygous for the TRα1R384C mutation, which confers receptor-mediated hypothyroidism. These mice display abnormalities in several autonomic functions, which was partially attributed to a developmental defect in hypothalamic parvalbumin neurons. However, whether other cell types in the hypothalamus are similarly affected remains unknown. Here, we used single-nucleus RNA sequencing to obtain an unbiased view on the importance of TRα1 for hypothalamic development and cellular diversity. Our data show that defective TRα1 signaling has surprisingly little effect on the development of hypothalamic neuronal populations, but it heavily affects hypothalamic oligodendrocytes. Using selective reactivation of the mutant TRα1 during specific developmental periods, we find that early postnatal thyroid hormone action seems to be crucial for proper hypothalamic oligodendrocyte maturation. Taken together, our findings underline the well-known importance of postnatal thyroid health for brain development and provide an unbiased roadmap for the identification of cellular targets of TRα1 action in mouse hypothalamic development.

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“…In instances of SLC16A2 mutation, the dysfunction of MCT8 results in insufficient intracellular levels of T3 in the presence of increased serum free levels, which results in hypomyelination and the severe psychomotor retardation seen in Allan-Herndon-Dudley syndrome (AHDS) ( Friesema et al, 2004 ; Armour et al, 2015 ; Valcárcel-Hernández et al, 2022 ). MCT8 dysfunction, as a prerequisite of AHDS, is supported by limited pre-clinical data from mouse models and clinical trials in AHDS patients and when treated with the TH analog 3,5-diiodothyropropionic acid (DITPA) resulted in amelioration of peripheral hyperthyroidism and overall hypermetabolism ( Verge et al, 2012 ; Ferrara et al, 2015 ).…”

Section: Thyroid Hormone Signaling In Mct8-deficient Circumstancesmentioning

confidence: 99%

Thyroid hormone-dependent oligodendroglial cell lineage genomic and non-genomic signaling through integrin receptors

et al. 2022

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Multiple sclerosis (MS) is a heterogeneous autoimmune disease whereby the pathological sequelae evolve from oligodendrocytes (OLs) within the central nervous system and are targeted by the immune system, which causes widespread white matter pathology and results in neuronal dysfunction and neurological impairment. The progression of this disease is facilitated by a failure in remyelination following chronic demyelination. One mediator of remyelination is thyroid hormone (TH), whose reliance on monocarboxylate transporter 8 (MCT8) was recently defined. MCT8 facilitates the entry of THs into oligodendrocyte progenitor cell (OPC) and pre-myelinating oligodendrocytes (pre-OLs). Patients with MS may exhibit downregulated MCT8 near inflammatory lesions, which emphasizes an inhibition of TH signaling and subsequent downstream targeted pathways such as phosphoinositide 3-kinase (PI3K)-Akt. However, the role of the closely related mammalian target of rapamycin (mTOR) in pre-OLs during neuroinflammation may also be central to the remyelination process and is governed by various growth promoting signals. Recent research indicates that this may be reliant on TH-dependent signaling through β1-integrins. This review identifies genomic and non-genomic signaling that is regulated through mTOR in TH-responsive pre-OLs and mature OLs in mouse models of MS. This review critiques data that implicates non-genomic Akt and mTOR signaling in response to TH-dependent integrin receptor activation in pre-OLs. We have also examined whether this can drive remyelination in the context of neuroinflammation and associated sequelae. Importantly, we outline how novel therapeutic small molecules are being designed to target integrin receptors on oligodendroglial lineage cells and whether these are viable therapeutic options for future use in clinical trials for MS.

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Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development

Cited by 12 publications

References 37 publications

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

TRIAC Treatment Improves Impaired Brain Network Function and White Matter Loss in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice

Single-cell RNA-based phenotyping reveals a pivotal role of thyroid hormone receptor alpha for hypothalamic development

Thyroid hormone-dependent oligodendroglial cell lineage genomic and non-genomic signaling through integrin receptors

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