Adult Mice Lacking Mct8 and Dio2 Proteins Present Alterations in Peripheral Thyroid Hormone Levels and Severe Brain and Motor Skill Impairments

被引:43
作者
Barez-Lopez, Soledad [1 ,2 ,4 ]
Grijota-Martinez, Carmen [1 ,2 ]
Auso, Eva [1 ,3 ]
Fernandez-de Frutos, Mario [1 ,5 ]
Montero-Pedrazuela, Ana [1 ]
Guadano-Ferraz, Ana [1 ,2 ]
机构
[1] Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain
[2] Inst Salud Carlos III, Unit 708, Ctr Biomed Res Rare Dis Ciberer, Madrid, Spain
[3] Univ Alicante, Dept Opt Farmacol & Anat, Alicante, Spain
[4] Univ Bristol, Sch Clin Sci, Dorothy Hodgkin Bldg, Bristol, Avon, England
[5] IMDEA Res Inst Food & Hlth Sci, Madrid, Spain
关键词
Mct8; deficiency; deiodinase type 2; mouse model; motor skills impairments; histological brain impairments; MONOCARBOXYLATE TRANSPORTER 8; PARVALBUMIN IMMUNOREACTIVITY; FUNCTIONAL-CHARACTERIZATION; GENE-EXPRESSION; DUDLEY-SYNDROME; PROMINENT ROLE; DEFICIENCY; MUTATIONS; PHENOTYPE; CORTEX;
D O I
10.1089/thy.2019.0068
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) lead to peripheral hyperthyroidism and profound psychomotor alterations in humans. Mice lacking Mct8 present peripheral hyperthyroidism but no gross neurological abnormalities due to brain compensatory mechanisms involving the enzyme deiodinase type 2 (Dio2). Methods: Here we have analyzed the endocrine and neurologic phenotype of mice lacking both Mct8 and Dio2 at three and six months of age. Thyroxine (T4) and 3,5,3 ' triiodothyronine (T3) levels/content were measured by specific radioimmunoassays; motor skill performance was evaluated by the footprint, rotarod, four limb hanging wire, and balance beam tests; and brain histological analysis was performed by immunostaining for neurofilament and parvalbumin. Results: We have found that this mouse model presents peripheral hyperthyroidism and brain hypothyroidism. Interestingly, the severity of the brain hypothyroidism seems permanent and varies across regions, with the striatum being a particularly affected area. We have also found brain alterations at the histological level compatible with TH deficiency and impaired motor skills. Conclusions: These findings indicate the potential of Mct8/Dio2-deficient mice to represent a model for human MCT8 deficiency, to understand the mechanisms underlying its pathophysiology, and ultimately design therapeutic interventions for human patients.
引用
收藏
页码:1669 / 1682
页数:14
相关论文
共 64 条
[1]  
Allan W, 1944, AM J MENT DEF, V48, P325
[2]  
[Anonymous], BEHAV PHENOTYPING TR
[3]   Age-associated motor and visuo-spatial learning phenotype in Dyrk1A heterozygous mutant mice [J].
Arque, Gloria ;
Martinez de Lagran, Maria ;
Arbones, Maria L. ;
Dierssen, Mara .
NEUROBIOLOGY OF DISEASE, 2009, 36 (02) :312-319
[4]   Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain [J].
Barez-Lopez, Soledad ;
Hartley, Meredith D. ;
Grijota-Martinez, Carmen ;
Scanlan, Thomas S. ;
Guadano-Ferraz, Ana .
THYROID, 2018, 28 (09) :1211-1220
[5]   Thyroid Hormone Economy in the Perinatal Mouse Brain: Implications for Cerebral Cortex Development [J].
Barez-Lopez, Soledad ;
Jesus Obregon, Maria ;
Bernal, Juan ;
Guadano-Ferraz, Ana .
CEREBRAL CORTEX, 2018, 28 (05) :1783-1793
[6]   Abnormal Motor Phenotype at Adult Stages in Mice Lacking Type 2 Deiodinase [J].
Barez-Lopez, Soledad ;
Bosch-Garcia, Daniel ;
Gomez-Andres, David ;
Pulido-Valdeolivas, Irene ;
Montero-Pedrazuela, Ana ;
Obregon, Maria Jesus ;
Guadano-Ferraz, Ana .
PLOS ONE, 2014, 9 (08)
[7]   Distribution of parvalbumin immunoreactivity in the neocortex of hypothyroid adult rats [J].
Berbel, P ;
Marco, P ;
Cerezo, JR ;
DeFelipe, J .
NEUROSCIENCE LETTERS, 1996, 204 (1-2) :65-68
[8]   Thyroid hormone transporters-functions and clinical implications [J].
Bernal, Juan ;
Guadano-Ferraz, Ana ;
Morte, Beatriz .
NATURE REVIEWS ENDOCRINOLOGY, 2015, 11 (07) :406-417
[9]   Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8 [J].
Biebermann, H ;
Ambrugger, P ;
Tarnow, P ;
von Moers, A ;
Schweizer, U ;
Grueters, A .
EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2005, 153 (03) :359-366
[10]   Allane-Herndone-Dudley syndrome (AHDS) in two consecutive generations caused by a missense MCT8 gene mutation. Phenotypic variability with the presence of normal serum T3 levels [J].
Boccone, Loredana ;
Dessi, Valentina ;
Meloni, Antonella ;
Loudianos, Georgios .
EUROPEAN JOURNAL OF MEDICAL GENETICS, 2013, 56 (04) :207-210