McAninch Elizabeth A, Jo Sungro, Preite Nailliw Z, Farkas Erzsébet, Mohácsik Petra, Fekete Csaba, Egri Péter, Gereben Balázs, Li Yan, Deng Youping, Patti Mary-Elizabeth, Zevenbergen Chantal, Peeters Robin P, Mash Deborah C, Bianco Antonio C
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.
J Clin Endocrinol Metab. 2015 Mar;100(3):920-33. doi: 10.1210/jc.2014-4092. Epub 2015 Jan 8.
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.
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.
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.
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.
已知编码激活型脱碘酶（Thr92Ala-D2）的基因中的一种常见多态性与数百万甲状腺功能减退患者的生活质量以及几种器官特异性疾病有关。这种多态性导致D2分子内单个氨基酸发生变化，而D2分子对泛素化和蛋白酶体降解的敏感性在此处受到调控。
确定Thr92Ala-D2多态性携带者相关疾病的分子机制。
设计、研究地点、患者：对19份人类大脑皮质尸检样本进行微阵列分析，以通过稳定表达Thr92或Ala92 D2的HEK-293细胞模型为分子研究奠定基础。
Thr92Ala-D2携带者的大脑皮质呈现出一种转录指纹，其中包括与中枢神经系统疾病、泛素、线粒体功能障碍（编码线粒体蛋白的染色体基因）、炎症、细胞凋亡、DNA修复和生长因子信号传导相关的基因集。在表达Ala92-D2的HEK-293细胞中也发现了类似的结果，并且在这两种情况下均没有证据表明甲状腺激素信号传导受到影响，即T3反应性基因的表达水平未发生变化，但其他一些基因受到了差异调节。综合微阵列分析（大脑/细胞）导致开发出一种81基因分类器，该分类器能够正确预测纯合大脑样本的基因型。与Thr92-D2相比，Ala92-D2表现出更长的半衰期，并且始终定位于高尔基体中。在表达Ala92-D2的细胞中，一些与高尔基体相关的基因被下调，但在用抗氧化剂N-乙酰半胱氨酸处理24小时后恢复正常。
Ala92-D2在高尔基体中积累，其存在和/或随之而来的氧化应激会破坏基本细胞功能并增加细胞凋亡前期。这些发现让人联想到在其他神经退行性疾病（如亨廷顿舞蹈症）中观察到的疾病机制，并且可能导致受影响携带者未解决的神经认知症状。
