Elizabeth A McAninch1, Sungro Jo, Nailliw Z Preite, Erzsébet Farkas, Petra Mohácsik, Csaba Fekete, Péter Egri, Balázs Gereben, Yan Li, Youping Deng, Mary-Elizabeth Patti, Chantal Zevenbergen, Robin P Peeters, Deborah C Mash, Antonio C Bianco. 1. Division of Endocrinology and Metabolism (E.A.M., S.J., N.Z.P., A.C.B.), Rush University Medical Center, Chicago, Illinois 60612; Department of Endocrine Neurobiology (E.F., P.M., C.F., P.E., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083, Hungary; Péter Pázmány Catholic University (E.F.), Multidisciplinary Doctoral School of Sciences and Technology, Budapest, H-1083 Hungary; Semmelweis University (P.M., P.E.), János Szentágothai PhD School of Neurosciences, Budapest, H-1085 Hungary; Division of Endocrinology (C.F.), Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts 02111; Department of Medicine (Y.L., Y.D.), Rush University Medical Center, Chicago, Illinois 60612; Joslin Diabetes Center (M.E.P.), Harvard Medical School, Boston, Massachusetts 02215; Division of Endocrinology (C.Z., R.P.P.), Rotterdam Thyroid Center, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; and Department of Neurology (D.C.M.), University of Miami Miller School of Medicine, Miami, Florida 33136.
Abstract
CONTEXT: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. OBJECTIVE: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. DESIGN, SETTING, PATIENTS: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. RESULTS: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. CONCLUSIONS: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.
CONTEXT: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. OBJECTIVE: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. DESIGN, SETTING, PATIENTS: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. RESULTS: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. CONCLUSIONS:Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.
Authors: Sungro Jo; Imre Kalló; Zsuzsanna Bardóczi; Rafael Arrojo e Drigo; Anikó Zeöld; Zsolt Liposits; Anthony Oliva; Vance P Lemmon; John L Bixby; Balázs Gereben; Antonio C Bianco Journal: J Neurosci Date: 2012-06-20 Impact factor: 6.167
Authors: Luis Henrique Canani; Clarissa Capp; José Miguel Dora; Erika L Souza Meyer; Márcia S Wagner; John W Harney; P Reed Larsen; Jorge L Gross; Antonio C Bianco; Ana Luiza Maia Journal: J Clin Endocrinol Metab Date: 2005-03-29 Impact factor: 5.958
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: Alice S Chen-Plotkin; William T Hu; Andrew Siderowf; Daniel Weintraub; Rachel Goldmann Gross; Howard I Hurtig; Sharon X Xie; Steven E Arnold; Murray Grossman; Christopher M Clark; Leslie M Shaw; Leo McCluskey; Lauren Elman; Vivianna M Van Deerlin; Virginia M-Y Lee; Holly Soares; John Q Trojanowski Journal: Ann Neurol Date: 2010-11-29 Impact factor: 10.422
Authors: Sherita H Golden; Karen A Robinson; Ian Saldanha; Blair Anton; Paul W Ladenson Journal: J Clin Endocrinol Metab Date: 2009-06 Impact factor: 5.958
Authors: Robin P Peeters; Hans van Toor; Willem Klootwijk; Yolanda B de Rijke; George G J M Kuiper; Andre G Uitterlinden; Theo J Visser Journal: J Clin Endocrinol Metab Date: 2003-06 Impact factor: 5.958
Authors: Antonio C Bianco; Alexandra Dumitrescu; Balázs Gereben; Miriam O Ribeiro; Tatiana L Fonseca; Gustavo W Fernandes; Barbara M L C Bocco Journal: Endocr Rev Date: 2019-08-01 Impact factor: 19.871
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 Journal: J Clin Invest Date: 2018-12-03 Impact factor: 14.808