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

Página do item simplificado
dc.contributor.authorJo S.
dc.contributor.authorFonseca T.L.
dc.contributor.authorBocco B.M.L.C.
dc.contributor.authorFernandes G.W.
dc.contributor.authorMcAninch E.A.
dc.contributor.authorBolin A.P.
dc.contributor.authorDa Conceicao R.R.
dc.contributor.authorWerneck-De-Castro J.P.
dc.contributor.authorIgnacio D.L.
dc.contributor.authorEgri P.
dc.contributor.authorNemeth D.
dc.contributor.authorFekete C.
dc.contributor.authorBernardi M.M.
dc.contributor.authorLeitch V.D.
dc.contributor.authorMannan N.S.
dc.contributor.authorCurry K.F.
dc.contributor.authorButterfield N.C.
dc.contributor.authorBassett J.H.D.
dc.contributor.authorWilliams G.R.
dc.contributor.authorGereben B.
dc.contributor.authorRibeiro M.O.
dc.contributor.authorBianco A.C.
dc.date.accessioned2024-03-12T23:54:07Z
dc.date.available2024-03-12T23:54:07Z
dc.date.issued2019
dc.description.abstract© 2019 American Society for Clinical Investigation. All rights reserved.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.
dc.description.issuenumber1
dc.description.volume129
dc.identifier.doi10.1172/JCI123176
dc.identifier.issn1558-8238
dc.identifier.urihttps://dspace.mackenzie.br/handle/10899/35320
dc.relation.ispartofJournal of Clinical Investigation
dc.rightsAcesso Aberto
dc.titleType 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain
dc.typeArtigo
local.scopus.citations70
local.scopus.eid2-s2.0-85059425044
local.scopus.subjectAmino Acid Substitution
local.scopus.subjectAnimals
local.scopus.subjectBrain
local.scopus.subjectEndoplasmic Reticulum
local.scopus.subjectEndoplasmic Reticulum Stress
local.scopus.subjectGolgi Apparatus
local.scopus.subjectHEK293 Cells
local.scopus.subjectHumans
local.scopus.subjectHypothyroidism
local.scopus.subjectIodide Peroxidase
local.scopus.subjectMice
local.scopus.subjectMice, Transgenic
local.scopus.subjectMutation, Missense
local.scopus.subjectPolymorphism, Genetic
local.scopus.subjectThyroxine
local.scopus.subjectTriiodothyronine
local.scopus.subjectUnfolded Protein Response
local.scopus.updated2024-05-01
local.scopus.urlhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85059425044&origin=inward
Arquivos
Coleções
Artigos de periódico