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Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 Jan 02; Vol. 129 (1), pp. 230-245. Date of Electronic Publication: 2018 Dec 03. - Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Amino Acid Substitution
Animals
Endoplasmic Reticulum enzymology
Endoplasmic Reticulum genetics
Golgi Apparatus enzymology
Golgi Apparatus genetics
HEK293 Cells
Humans
Mice
Mice, Transgenic
Mutation, Missense
Thyroxine therapeutic use
Triiodothyronine therapeutic use
Iodothyronine Deiodinase Type II
Brain enzymology
Brain pathology
Endoplasmic Reticulum Stress
Hypothyroidism drug therapy
Hypothyroidism enzymology
Hypothyroidism genetics
Hypothyroidism pathology
Iodide Peroxidase genetics
Iodide Peroxidase metabolism
Polymorphism, Genetic
Unfolded Protein Response
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 30352046
- Full Text :
- https://doi.org/10.1172/JCI123176