Imperial College London
Alternate

Professor Duncan Bassett

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Professor of Endocrinology
 
 
 
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Contact

 

+44 (0)20 3313 4613d.bassett Website

 
 
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Location

 

10N6 Commomwealth BuildingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Jo:2019:10.1172/JCI123176,
author = {Jo, S and Fonseca, TL and Da, Costa Bocco BM and Fernandes, GW and McAninch, EA and Bolin, AP and Da, Conceição RR and De, Castro JPW and Ignacio, DL and Egri, P and Németh, D and Fekete, C and Bernardi, MM and Leitch, VD and Mannan, NS and Curry, KF and Butterfield, NC and Bassett, JHD and Williams, GR and Gereben, B and Ribeiro, MO and Bianco, AC},
doi = {10.1172/JCI123176},
journal = {Journal of Clinical Investigation},
pages = {230--245},
title = {Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain},
url = {http://dx.doi.org/10.1172/JCI123176},
volume = {129},
year = {2019}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by the 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 endoplasmic reticulum 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, all of 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.
AU  - Jo,S
AU  - Fonseca,TL
AU  - Da,Costa Bocco BM
AU  - Fernandes,GW
AU  - McAninch,EA
AU  - Bolin,AP
AU  - Da,Conceição RR
AU  - De,Castro JPW
AU  - Ignacio,DL
AU  - Egri,P
AU  - Németh,D
AU  - Fekete,C
AU  - Bernardi,MM
AU  - Leitch,VD
AU  - Mannan,NS
AU  - Curry,KF
AU  - Butterfield,NC
AU  - Bassett,JHD
AU  - Williams,GR
AU  - Gereben,B
AU  - Ribeiro,MO
AU  - Bianco,AC
DO  - 10.1172/JCI123176
EP  - 245
PY  - 2019///
SN  - 0021-9738
SP  - 230
TI  - Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
T2  - Journal of Clinical Investigation
UR  - http://dx.doi.org/10.1172/JCI123176
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30352046
UR  - http://hdl.handle.net/10044/1/64004
VL  - 129
ER  -
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