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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

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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 6

Impaired new social recognition in Ala92-Dio2 mouse.

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Impaired new social recognition in Ala92-Dio2 mouse.
SI memory test disp...
SI memory test displayed as preference index (%) of Thr92-Dio2 (Thr) and Ala92-Dio2 (Ala) mice. (A and B) Intact animals. (C and D) Intact+LT3 animals. (E and F) Intact+4-PBA animals. (G and H) Hypothyroid animals. (I and J) Hypothyroid+LT4 animals. (K–L) Hypothyroid+LT4+LT3 animals. (A, C, E, G, I, and K) 3-hour recall. (B, D, F, H, J, and L) 24-hour recall. Values are shown in a box-and-whiskers plot indicating median and quartiles. Statistical analysis used was Mann-Whitney U test. n = 5–11/group. **P ≤ 0.01; ***P ≤ 0.001.
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