A Deiodinase Polymorphism Causes ER-Stress And Hypothyroidism In The Brain
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PROVIDER: PRJNA488825 | ENA |
REPOSITORIES: ENA
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Project description:Expression data from different brain regions of mice Discrete brain areas were studied using an unbiased whole-transcript microarray approach (Ala92-Dio2 homozygotes vs Thr92-Dio2 homozygotes)
2018-09-01 | GSE119351 | GEO
Project description:Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.
| S-EPMC6307951 | biostudies-literature
Project description:An imbalance in thyroid hormones (THs) is associated with reversible dementia and Alzheimer’s disease (AD) pathogenesis. Whether hypothyroidism occurs in AD brains and how it affects AD pathology remain largely unknown. Here, we find that reduced conversion of thyroxine (T4) to tri-iodothyronine (T3) in the brain by decreased iodothyronine deiodinase 2 (DIO2) leads to hippocampal hypothyroidism in early AD model mice prior to TH changes in the blood. A TH deficiency causes immune tolerance with decreased phagocytic activity in microglia, thereby aggravating AD pathology. We demonstrate that microglial ecto-5’-nucleotidase (CD73) is reduced in the hypothyroid state and that its inhibition contributes to immune tolerance in microglia. Thus, our data define a molecular mechanism through which decreased conversion of T4 to T3 in the early AD brain, and consequent brain hypothyroidism causes microglial dysfunction and exacerbates AD pathology.
2023-09-01 | GSE219130 | GEO
Project description:An imbalance in thyroid hormones (THs) is associated with reversible dementia and Alzheimer’s disease (AD) pathogenesis. Whether hypothyroidism occurs in AD brains and how it affects AD pathology remain largely unknown. Here, we find that reduced conversion of thyroxine (T4) to tri-iodothyronine (T3) in the brain by decreased iodothyronine deiodinase 2 (DIO2) leads to hippocampal hypothyroidism in early AD model mice prior to TH changes in the blood. A TH deficiency causes immune tolerance with decreased phagocytic activity in microglia, thereby aggravating AD pathology. We demonstrate that microglial ecto-5’-nucleotidase (CD73) is reduced in the hypothyroid state and that its inhibition contributes to immune tolerance in microglia. Thus, our data define a molecular mechanism through which decreased conversion of T4 to T3 in the early AD brain, and consequent brain hypothyroidism causes microglial dysfunction and exacerbates AD pathology.
2023-09-01 | GSE219129 | GEO
Project description:The monocarboxylate transporter 8 (Mct8) protein is a primary T4 and T3 (TH) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alters thyroid function and thyroid hormone metabolism, and severely impairs neurodevelopment (Allan-Herndon-Dudley syndrome, AHDS). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is thought that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase (D2). The Slc16a2/Slco1c1 (MO) and Slc16a2/Dio2 (MD) double knock out mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, would be more approriate models of AHDS. The goal of this work was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KOs.
2020-12-15 | GSE155185 | GEO
Project description:Congenital hypothyroidism is a genetic condition in which the thyroid gland fails to produce sufficient thyroid hormone (TH), resulting in metabolic dysfunction and growth retardation. Xb130-/- mice exhibit perturbations of thyrocyte cytoskeleton and polarity, develop postnatal transient growth retardation due to congenital hypothyroidism and leading to multinodular goiter in elderly. To determine the underlying mechanisms, we performed transcriptomic analyses on thyroid glands of mice at three age points – week 2 (W2, before visible growth retardation), W4 (at the nadir of growth), and W12 (immediately before full growth recovery. We compared gene expression between Xb130+/+ and Xb130-/- mice.
2024-10-12 | GSE197052 | GEO
Project description:Purpose of reviewTo assess new findings and clinical implications of deiodinase gene polymorphism. Deiodinases are enzymes that can activate or inactivate thyroid hormone molecules. Whereas the types 1 and 2 deiodinase (D1 and D2) activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3) via deiodination of T4's outer ring, D1 and D3 inactivate both T4 and T3 and terminate thyroid hormone action via deiodination of T4's inner molecular ring. A number of polymorphisms have been identified in the three deiodinase genes; the most investigated and likely to have clinical relevance is the Thr92 substitution for Ala substitution in DIO2 (Thr92Ala-DIO2). There are a number of reports describing the association between the Thr92Ala-DIO2 polymorphism and clinical syndromes that include hypertension, type 2 diabetes, mental disorders, lung injury, bone turnover, and autoimmune thyroid disease; but these associations have not been reproduced in all population studies.Recent findingsA new report indicates that carriers of the Thr92Ala-DIO2 polymorphism exhibit lower D2 catalytic activity and localized/systemic hypothyroidism. This could explain why certain groups of levothyroxine-treated hypothyroid patients have improved quality of life when also treated with liothyronine (LT3). Furthermore, Ala92-D2 was abnormally found in the Golgi apparatus, what could constitute a disease mechanism independent of T3 signaling. Indeed, brain samples of Thr92Ala-DIO2 carriers exhibit gene profiles suggestive of brain degenerative disease. In addition, African American carriers of Thr92Ala-DIO2 exhibit an about 30% higher risk of developing Alzheimer's disease.SummaryThe finding of deiodinase polymorphisms that can diminish thyroid hormone signaling and/or disrupt normal cellular function opens the door to customized treatment of hypothyroidism. Future studies should explore how the racial background modulates the clinical relevance of the Thr92Ala-DIO2 gene polymorphism.
| S-EPMC6571023 | biostudies-literature
Project description:Microbial Features in Pregnant Women with Hypothyroidism
| PRJEB38373 | ENA
Project description:Children with congenital hypothyroidism (1 in every ~2,500 live births) may develop a dramatic neurological, muscle-skeleton, and metabolic syndrome due to insufficient thyroid hormone (TH) signaling during development 1-3. While the mechanisms involved remain largely unknown, it is well established that the condition is irreversible if treatment is not initiated during the immediate post-natal period. Here we used high-throughput genomic and epigenomic techniques (Hi-C) to generate high-resolution, genome-wide 3D maps of chromatin interaction in mice with developmental liver-specific hypothyroidism (caused by Dio2 inactivation). The neonatal disruption of hepatic TH signaling only minimally affected genomic compartmentalization but caused substantial rearrangements (e.g. shifting or splitting) in thousands of topologically associating domains (TADs). The rearranged TADs contained DNA sites of hypermethylation, areas of reduced chromatin accessibility, and hundreds of repressed genes. In many instances, the enhancer-promoter (E-P) interaction in key repressed genes had been weakened, explaining the permanent change in how the liver handles excess fat or alcohol in the adult mouse 4-6.
2025-01-01 | GSE252574 | GEO
Project description:proteomics of hypothyroidism during first half of pregnancy (32 samples)
2024-12-18 | PXD058969 |