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

Autor(es):Mostrar menos -

Jo, Sungro ^[1] ; Fonseca, Tatiana L. ^[2] ; Bocco, Barbara M. L. C. ^[2] ; Fernandes, Gustavo W. ^[2] ; McAninch, Elizabeth A. ^[1] ; Bolin, Anaysa P. ^{[3, 1]} ; Da Conceicao, Rodrigo R. ^{[1, 4]} ; Werneck-de-Castro, Joao Pedro ^[1] ; Ignacio, Daniele L. ^[1] ; Egri, Peter ^[5] ; Nemeth, Dorottya ^[5] ; Fekete, Csaba ^[5] ; Bernardi, Maria Martha ^[6] ; Leitch, Victoria D. ^[7] ; Mannan, Naila S. ^[7] ; Curry, Katharine F. ^[7] ; Butterfield, Natalie C. ^[7] ; Bassett, J. H. Duncan ^[7] ; Williams, Graham R. ^[7] ; Gereben, Balazs ^[5] ; Ribeiro, Miriam O. ^[8] ; Bianco, Antonio C. ^[2]

Afiliação do(s) autor(es)

^[1] Rush Univ, Med Ctr, Div Endocrinol & Metab, Chicago, IL 60612 - USA

^[2] Univ Chicago, Dept Med, Sect Adult & Pediat Endocrinol, Diabet & Metab, 5841 S Maryland Ave, MC1027, Room M267, Chicago, IL 60637 - USA

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, Dept Med, Lab Mol & Translat Endocrinol, Sao Paulo, SP - Brazil

^[5] Hungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest - Hungary

^[6] Univ Paulista, Grad Program Environm & Expt Pathol, Grad Program Dent, Sao Paulo, SP - Brazil

^[7] Imperial Coll London, Dept Med, Mol Endocrinol Lab, London - England

^[8] Univ Prebiteriana Mackenzie, Dev Disorders Program, Ctr Biol Sci & Hlth, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Clinical Investigation; v. 129, n. 1, p. 230-245, JAN 2 2019.
• Citações Web of Science: 11

Resumo

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. (AU)

• Processo FAPESP: 17/18277-0 - Correlação entre o polimorfismo Thr92Ala da enzima iodotironina desiodase do tipo 2 (D2) e comportamento.
• Beneficiário: Miriam Oliveira Ribeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular