Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
Sungro Jo, … , Miriam O. Ribeiro, Antonio C. Bianco
Sungro Jo, … , Miriam O. Ribeiro, Antonio C. Bianco
Published October 23, 2018
Citation Information: J Clin Invest. 2019;129(1):230-245. https://doi.org/10.1172/JCI123176.
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Research Article Endocrinology Metabolism

Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain

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.

Authors

Sungro Jo, Tatiana L. Fonseca, Barbara M. L. C. Bocco, Gustavo W. Fernandes, Elizabeth A. McAninch, Anaysa P. Bolin, Rodrigo R. Da Conceição, Joao Pedro Werneck-de-Castro, Daniele L. Ignacio, Péter Egri, Dorottya Németh, Csaba Fekete, Maria Martha Bernardi, Victoria D. Leitch, Naila S. Mannan, Katharine F. Curry, Natalie C. Butterfield, J.H. Duncan Bassett, Graham R. Williams, Balázs Gereben, Miriam O. Ribeiro, Antonio C. Bianco

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Figure 4

ER stress in Ala92-Dio2 cerebral cortex and slower rate of T4 to T3 conversion in Ala92-D2 expressing cells.

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ER stress in Ala92-Dio2 cerebral cortex and slower rate of T4 to T3 conv...
(A) Western blot of cerebral cortex sonicates of Thr92-Dio2 (Thr) and Ala92-Dio2 (Ala) mice utilizing the indicated antibodies; each lane represents an independent mouse sample. (B) Quantification of uncleaved and cleaved ATF6. (C) In vivo deiodination in intact Thr92-D2HY–expressing (Thr) or Ala92-D2HY–expressing (Ala) cells. (D) Immunoprecipitation followed by Western blot of T and A cells utilizing α-YFP and α-cyclophilin B. (E) In vitro deiodination in T and A cell sonicates. (F) Same as C, except that cells were treated for 24 hours with 500 μM 4-PBA or 10 μg/ml cholesterol. Values are shown in a box-and-whiskers plot indicating median and quartiles or mean ± SEM. n = 3–10/group. Statistical analysis used was the Mann-Whitney U test or the Kruskall-Wallis test, followed by the Dunn’s multiple comparison test. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.