Type 2 deiodinase polymorphism causes ER stress... - Thyroid UK

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

virtualreality profile image
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Found this paper by Bianco and colleagues - hopefully more fuel for those with the DIO2 variation needing to access T3 treatment.

Link: jci.org/articles/view/123176

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.

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2 Replies

Looks interesting, though quite a bit of it is beyond me!

Musicmonkey profile image
Musicmonkey

As someone who has the faulty gene polymorphism DIO2, I am very interested in this, but because I have it I find this very detailed scientific study too complex to understand!

Is there anyone who can simplify the study and its findings please?

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