Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function
Thyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong...
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MDPI AG
2023-10-01
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| author | Devon Siemes Pieter Vancamp Boyka Markova Philippa Spangenberg Olga Shevchuk Bente Siebels Hartmut Schlüter Steffen Mayerl Heike Heuer Daniel Robert Engel |
| author_facet | Devon Siemes Pieter Vancamp Boyka Markova Philippa Spangenberg Olga Shevchuk Bente Siebels Hartmut Schlüter Steffen Mayerl Heike Heuer Daniel Robert Engel |
| author_sort | Devon Siemes |
| collection | DOAJ |
| description | Thyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong central TH deprivation, locomotor impairments and similar histo-morphological features as seen in MCT8 patients. The pathways that cause these neuro-motor symptoms are poorly understood. In this paper, we performed proteome analysis of brain sections comprising cortical and striatal areas of 21-day-old WT and DKO mice. We detected over 2900 proteins by liquid chromatography mass spectrometry, 67 of which were significantly different between the genotypes. The comparison of the proteomic and published RNA-sequencing data showed a significant overlap between alterations in both datasets. In line with previous observations, DKO animals exhibited decreased myelin-associated protein expression and altered protein levels of well-established neuronal TH-regulated targets. As one intriguing new candidate, we unraveled and confirmed the reduced protein and mRNA expression of Pde10a, a striatal enzyme critically involved in dopamine receptor signaling, in DKO mice. As altered PDE10A activities are linked to dystonia, reduced basal ganglia PDE10A expression may represent a key pathogenic pathway underlying human MCT8 deficiency. |
| first_indexed | 2024-03-10T21:21:47Z |
| format | Article |
| id | doaj.art-9daf7929363549849adde0c41515077e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T21:21:47Z |
| publishDate | 2023-10-01 |
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| spelling | doaj.art-9daf7929363549849adde0c41515077e2023-11-19T16:02:51ZengMDPI AGCells2073-44092023-10-011220248710.3390/cells12202487Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor FunctionDevon Siemes0Pieter Vancamp1Boyka Markova2Philippa Spangenberg3Olga Shevchuk4Bente Siebels5Hartmut Schlüter6Steffen Mayerl7Heike Heuer8Daniel Robert Engel9Department of Immunodynamics, Institute for Experimental Immunology and Imaging, University Duisburg-Essen, 45141 Essen, GermanyDepartment of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, GermanyDepartment of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, GermanyDepartment of Immunodynamics, Institute for Experimental Immunology and Imaging, University Duisburg-Essen, 45141 Essen, GermanyDepartment of Immunodynamics, Institute for Experimental Immunology and Imaging, University Duisburg-Essen, 45141 Essen, GermanySection Mass Spectrometric Proteomics, Diagnostic Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanySection Mass Spectrometric Proteomics, Diagnostic Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, GermanyDepartment of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, GermanyDepartment of Immunodynamics, Institute for Experimental Immunology and Imaging, University Duisburg-Essen, 45141 Essen, GermanyThyroid hormone (TH) transporter MCT8 deficiency causes severe locomotor disabilities likely due to insufficient TH transport across brain barriers and, consequently, compromised neural TH action. As an established animal model for this disease, Mct8/Oatp1c1 double knockout (DKO) mice exhibit strong central TH deprivation, locomotor impairments and similar histo-morphological features as seen in MCT8 patients. The pathways that cause these neuro-motor symptoms are poorly understood. In this paper, we performed proteome analysis of brain sections comprising cortical and striatal areas of 21-day-old WT and DKO mice. We detected over 2900 proteins by liquid chromatography mass spectrometry, 67 of which were significantly different between the genotypes. The comparison of the proteomic and published RNA-sequencing data showed a significant overlap between alterations in both datasets. In line with previous observations, DKO animals exhibited decreased myelin-associated protein expression and altered protein levels of well-established neuronal TH-regulated targets. As one intriguing new candidate, we unraveled and confirmed the reduced protein and mRNA expression of Pde10a, a striatal enzyme critically involved in dopamine receptor signaling, in DKO mice. As altered PDE10A activities are linked to dystonia, reduced basal ganglia PDE10A expression may represent a key pathogenic pathway underlying human MCT8 deficiency.https://www.mdpi.com/2073-4409/12/20/2487T4T3Slc16a2Slco1c1CNSmyelination |
| spellingShingle | Devon Siemes Pieter Vancamp Boyka Markova Philippa Spangenberg Olga Shevchuk Bente Siebels Hartmut Schlüter Steffen Mayerl Heike Heuer Daniel Robert Engel Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function Cells T4 T3 Slc16a2 Slco1c1 CNS myelination |
| title | Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function |
| title_full | Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function |
| title_fullStr | Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function |
| title_full_unstemmed | Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function |
| title_short | Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function |
| title_sort | proteome analysis of thyroid hormone transporter mct8 oatp1c1 deficient mice reveals novel dysregulated target molecules involved in locomotor function |
| topic | T4 T3 Slc16a2 Slco1c1 CNS myelination |
| url | https://www.mdpi.com/2073-4409/12/20/2487 |
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