Thyroid hormone transporter Mct8/Oatp1c1 deficiency compromises proper oligodendrocyte maturation in the mouse CNS

Mayerl, Steffen; Heuer, Heike

doi:10.1016/j.nbd.2023.106195

Cited by 4 publications

(3 citation statements)

References 43 publications

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“…A prominent observation is the downregulation of several myelin-associated proteins (Mog, Mag, Plp1 and Cnp), which fully reflects the myelination phenotype of DKO mice and AHDS patients [6,10]. Likewise, a reduced abundance of proteins known to be present within the oligodendroglia lineage (Bcas, Enpp6, Gltp, Sirt2 and Smpd3) is in agreement with a decreased number of oligodendrocytes in white and grey matter regions of DKO mice [9]. The decreased protein expression of several neurofilaments (Nefl, Nefm, Nefh and Ina1) are indicative for a disturbed neuronal maturation and might be linked to the reduced axon caliber observed in MCT8 patients and AHDS mouse models [6,12,25].…”

Section: Discussionmentioning

confidence: 57%

“…Likewise, mice deficient for the TH transporters Mct8 and Oatp1c1 (DKO) replicate many clinical features of human MCT8 deficiency. DKO mice show locomotor impairments, abnormal GABAergic interneuron development as well as a persistent hypomyelination due to insufficient TH supply to neurons and oligodendrocytes [6,9]. However, to which extent neuronal and myelination deficits cause the observed locomotor impairments in DKO mice remains a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

“…Mice with a concomitant inactivation of Mct8 and the T4-specific transporter Oatp1c1 (Mct8/Oatp1c1 knockout (DKO) mice) replicate the peripheral endocrine abnormalities of MCT8 patients and show a profound TH-deficient status in the CNS, thus representing an established animal model of AHDS [6]. DKO mice also display locomotor impairments as well as distinct histo-morphological alterations, such as impaired cortical GABAergic cell differentiation, delayed Purkinje cell dendritogenesis and persistent hypomyelination [6][7][8][9]. These observations align with results from MRI analyses and post-mortem brain samples derived from a MCT8-deficient patient [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Proteome Analysis of Thyroid Hormone Transporter Mct8/Oatp1c1-Deficient Mice Reveals Novel Dysregulated Target Molecules Involved in Locomotor Function

Siemes,

Vancamp,

Markova

et al. 2023

Cells

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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.

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