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 1

D2 recycles between Golgi apparatus and ER.

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D2 recycles between Golgi apparatus and ER. (A–F) Immunofluorescence of ...
(A–F) Immunofluorescence of Thr92-D2HY stably expressing cells using the indicated antibodies. On the far right is the Pearson’s plot for each immunofluorescence image. The right top number is the Pearson’s coefficient for that specific cell. Pearson’s coefficient was calculated as follows: Thr92-DIO2 × α-GM130 (0.32 ± 0.06); Ala92-DIO2 × α-GM130 (0.36 ± 0.07). (G–L) Same as A–F, except that cells stably express Ala92-D2HY. Arrows point to Golgi AlaD2 staining. Pearson’s coefficient: Thr92-DIO2 × α-p230 (0.33 ± 0.05); Ala92-DIO2 × α-p230 (0.65 ± 0.12; P < 0.01 versus Thr92-DIO2 × α-p230). (M and N) Thr92-D2HY (Thr) or Ala92-D2HY (Ala) pulldown, followed by Western blot analysis with the indicated antibodies. (O) Same as M and N, except that cells transiently express Δ18-D2HY. (P–R) Same as A–C except that cells transiently express Δ18-D2HY. (S) Pearson’s coefficient between the indicated D2 proteins and cis-Golgi marker GM130; Δ18-D2 is Δ18-D2HY (P–R). D2T is Thr92-D2HY (A–C). ΔC-D2T is Δ10C-Thr92-D2HY (T–V). ΔC-D2A is Δ10C-Ala92-D2HY (W–Y). (T–Y) Same as A–C, except that cells transiently express Δ10C-Thr92-D2HY or Δ10C-Ala92-D2HY. Original magnification, APO ×60/1.40 oil objective. Values are shown in box-and-whiskers plot indicating median and quartiles. n = 21/group. Statistical analysis used was Mann-Whitney U test in comparison with D2T. ***P ≤ 0.0001.